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Assunção, Gustavo, Nuno Gonçalves, and Paulo Menezes. "Bio-Inspired Modality Fusion for Active Speaker Detection." Applied Sciences 11, no. 8 (April 10, 2021): 3397. http://dx.doi.org/10.3390/app11083397.
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Human beings have developed fantastic abilities to integrate information from various sensory sources exploring their inherent complementarity. Perceptual capabilities are therefore heightened, enabling, for instance, the well-known "cocktail party" and McGurk effects, i.e., speech disambiguation from a panoply of sound signals. This fusion ability is also key in refining the perception of sound source location, as in distinguishing whose voice is being heard in a group conversation. Furthermore, neuroscience has successfully identified the superior colliculus region in the brain as the one responsible for this modality fusion, with a handful of biological models having been proposed to approach its underlying neurophysiological process. Deriving inspiration from one of these models, this paper presents a methodology for effectively fusing correlated auditory and visual information for active speaker detection. Such an ability can have a wide range of applications, from teleconferencing systems to social robotics. The detection approach initially routes auditory and visual information through two specialized neural network structures. The resulting embeddings are fused via a novel layer based on the superior colliculus, whose topological structure emulates spatial neuron cross-mapping of unimodal perceptual fields. The validation process employed two publicly available datasets, with achieved results confirming and greatly surpassing initial expectations.
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Pu, Jie, Yannis Panagakis, and Maja Pantic. "Active Speaker Detection and Localization in Videos Using Low-Rank and Kernelized Sparsity." IEEE Signal Processing Letters 27 (2020): 865–69. http://dx.doi.org/10.1109/lsp.2020.2996412.
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Lindstrom, Fredric, Keni Ren, Kerstin Persson Waye, and Haibo Li. "A comparison of two active‐speaker‐detection methods suitable for usage in noise dosimeter measurements." Journal of the Acoustical Society of America 123, no. 5 (May 2008): 3527. http://dx.doi.org/10.1121/1.2934471.
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Zhu, Ying-Xin, and Hao-Ran Jin. "Speaker Localization Based on Audio-Visual Bimodal Fusion." Journal of Advanced Computational Intelligence and Intelligent Informatics 25, no. 3 (May 20, 2021): 375–82. http://dx.doi.org/10.20965/jaciii.2021.p0375.
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The demand for fluency in human–computer interaction is on an increase globally; thus, the active localization of the speaker by the machine has become a problem worth exploring. Considering that the stability and accuracy of the single-mode localization method are low, while the multi-mode localization method can utilize the redundancy of information to improve accuracy and anti-interference, a speaker localization method based on voice and image multimodal fusion is proposed. First, the voice localization method based on time differences of arrival (TDOA) in a microphone array and the face detection method based on the AdaBoost algorithm are presented herein. Second, a multimodal fusion method based on spatiotemporal fusion of speech and image is proposed, and it uses a coordinate system converter and frame rate tracker. The proposed method was tested by positioning the speaker stand at 15 different points, and each point was tested 50 times. The experimental results demonstrate that there is a high accuracy when the speaker stands in front of the positioning system within a certain range.
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Stefanov, Kalin, Jonas Beskow, and Giampiero Salvi. "Self-Supervised Vision-Based Detection of the Active Speaker as Support for Socially Aware Language Acquisition." IEEE Transactions on Cognitive and Developmental Systems 12, no. 2 (June 2020): 250–59. http://dx.doi.org/10.1109/tcds.2019.2927941.
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DAI, Hai, Kean CHEN, Yang WANG, and Haoxin YU. "Fault detection method of secondary sound source in ANC system based on impedance characteristics." Xibei Gongye Daxue Xuebao/Journal of Northwestern Polytechnical University 40, no. 6 (December 2022): 1242–49. http://dx.doi.org/10.1051/jnwpu/20224061242.
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As an indispensable component in an active noise control system, the working states of the secondary sound sources affect directly noise reduction and the robustness of the system. Therefore, it is very crucial to detect the working states of the secondary sound sources in the process of active control in real time. In this study, a real-time fault detection method for secondary sound sources during the process of active control is presented, and the corresponding detection algorithm is numerically given and experimentally verified. By collecting the input voltage and output current of the speaker unit, the sound quality factor is calculated to comprehensively judge the working state of the secondary sound sources. The simulation and experimental results show that the present method is simple and has low computational cost, can accurately reflect accurately the working states of the secondary sound sources in real time, and provides a basis for judging the operation of the active noise control system.
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Ahmad, Zubair, Alquhayz, and Ditta. "Multimodal Speaker Diarization Using a Pre-Trained Audio-Visual Synchronization Model." Sensors 19, no. 23 (November 25, 2019): 5163. http://dx.doi.org/10.3390/s19235163.
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Speaker diarization systems aim to find ‘who spoke when?’ in multi-speaker recordings. The dataset usually consists of meetings, TV/talk shows, telephone and multi-party interaction recordings. In this paper, we propose a novel multimodal speaker diarization technique, which finds the active speaker through audio-visual synchronization model for diarization. A pre-trained audio-visual synchronization model is used to find the synchronization between a visible person and the respective audio. For that purpose, short video segments comprised of face-only regions are acquired using a face detection technique and are then fed to the pre-trained model. This model is a two streamed network which matches audio frames with their respective visual input segments. On the basis of high confidence video segments inferred by the model, the respective audio frames are used to train Gaussian mixture model (GMM)-based clusters. This method helps in generating speaker specific clusters with high probability. We tested our approach on a popular subset of AMI meeting corpus consisting of 5.4 h of recordings for audio and 5.8 h of different set of multimodal recordings. A significant improvement is noticed with the proposed method in term of DER when compared to conventional and fully supervised audio based speaker diarization. The results of the proposed technique are very close to the complex state-of-the art multimodal diarization which shows significance of such simple yet effective technique.
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Wang, Shaolei, Zhongyuan Wang, Wanxiang Che, Sendong Zhao, and Ting Liu. "Combining Self-supervised Learning and Active Learning for Disfluency Detection." ACM Transactions on Asian and Low-Resource Language Information Processing 21, no. 3 (May 31, 2022): 1–25. http://dx.doi.org/10.1145/3487290.
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Spoken language is fundamentally different from the written language in that it contains frequent disfluencies or parts of an utterance that are corrected by the speaker. Disfluency detection (removing these disfluencies) is desirable to clean the input for use in downstream NLP tasks. Most existing approaches to disfluency detection heavily rely on human-annotated data, which is scarce and expensive to obtain in practice. To tackle the training data bottleneck, in this work, we investigate methods for combining self-supervised learning and active learning for disfluency detection. First, we construct large-scale pseudo training data by randomly adding or deleting words from unlabeled data and propose two self-supervised pre-training tasks: (i) a tagging task to detect the added noisy words and (ii) sentence classification to distinguish original sentences from grammatically incorrect sentences. We then combine these two tasks to jointly pre-train a neural network. The pre-trained neural network is then fine-tuned using human-annotated disfluency detection training data. The self-supervised learning method can capture task-special knowledge for disfluency detection and achieve better performance when fine-tuning on a small annotated dataset compared to other supervised methods. However, limited in that the pseudo training data are generated based on simple heuristics and cannot fully cover all the disfluency patterns, there is still a performance gap compared to the supervised models trained on the full training dataset. We further explore how to bridge the performance gap by integrating active learning during the fine-tuning process. Active learning strives to reduce annotation costs by choosing the most critical examples to label and can address the weakness of self-supervised learning with a small annotated dataset. We show that by combining self-supervised learning with active learning, our model is able to match state-of-the-art performance with just about 10% of the original training data on both the commonly used English Switchboard test set and a set of in-house annotated Chinese data.
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Maltezou-Papastylianou, Constantina, Riccardo Russo, Denise Wallace, Chelsea Harmsworth, and Silke Paulmann. "Different stages of emotional prosody processing in healthy ageing–evidence from behavioural responses, ERPs, tDCS, and tRNS." PLOS ONE 17, no. 7 (July 21, 2022): e0270934. http://dx.doi.org/10.1371/journal.pone.0270934.
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Past research suggests that the ability to recognise the emotional intent of a speaker decreases as a function of age. Yet, few studies have looked at the underlying cause for this effect in a systematic way. This paper builds on the view that emotional prosody perception is a multi-stage process and explores which step of the recognition processing line is impaired in healthy ageing using time-sensitive event-related brain potentials (ERPs). Results suggest that early processes linked to salience detection as reflected in the P200 component and initial build-up of emotional representation as linked to a subsequent negative ERP component are largely unaffected in healthy ageing. The two groups show, however, emotional prosody recognition differences: older participants recognise emotional intentions of speakers less well than younger participants do. These findings were followed up by two neuro-stimulation studies specifically targeting the inferior frontal cortex to test if recognition improves during active stimulation relative to sham. Overall, results suggests that neither tDCS nor high-frequency tRNS stimulation at 2mA for 30 minutes facilitates emotional prosody recognition rates in healthy older adults.
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Lahemer, Elfituri S. F., and Ahmad Rad. "An Audio-Based SLAM for Indoor Environments: A Robotic Mixed Reality Presentation." Sensors 24, no. 9 (April 27, 2024): 2796. http://dx.doi.org/10.3390/s24092796.
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In this paper, we present a novel approach referred to as the audio-based virtual landmark-based HoloSLAM. This innovative method leverages a single sound source and microphone arrays to estimate the voice-printed speaker’s direction. The system allows an autonomous robot equipped with a single microphone array to navigate within indoor environments, interact with specific sound sources, and simultaneously determine its own location while mapping the environment. The proposed method does not require multiple audio sources in the environment nor sensor fusion to extract pertinent information and make accurate sound source estimations. Furthermore, the approach incorporates Robotic Mixed Reality using Microsoft HoloLens to superimpose landmarks, effectively mitigating the audio landmark-related issues of conventional audio-based landmark SLAM, particularly in situations where audio landmarks cannot be discerned, are limited in number, or are completely missing. The paper also evaluates an active speaker detection method, demonstrating its ability to achieve high accuracy in scenarios where audio data are the sole input. Real-time experiments validate the effectiveness of this method, emphasizing its precision and comprehensive mapping capabilities. The results of these experiments showcase the accuracy and efficiency of the proposed system, surpassing the constraints associated with traditional audio-based SLAM techniques, ultimately leading to a more detailed and precise mapping of the robot’s surroundings.
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Gong, Yanbin, Qian Zhang, Bobby H. P. NG, and Wei Li. "BreathMentor." Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies 6, no. 2 (July 4, 2022): 1–28. http://dx.doi.org/10.1145/3534595.
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Chronic Obstructive Pulmonary Disease (COPD) is currently the third major cause of death--more than three million people died from it in 2019. Given that COPD cannot be cured currently, immediate treatment is crucial. Pulmonary rehabilitation (PR) is widely used to prevent COPD deterioration. Patients are advised to undergo a PR at home to get sufficient treatment in time. Monitoring patients during home rehabilitation can help not only improve patient adherence but also collect data on patients' recovery progress from rehabilitation team's perspective. However, how to track if proper diaphragmatic breathing, an essential part of PR, is taken by a patient has remained challenging. The current monitoring solution still appears obtrusive as it requires the patient to wear two uncomfortable respiration belts. Alternatively, therapists need to monitor the patients remotely through several cameras, which consumes substantial medical resources and causes privacy issues. In this work, we present BreathMentor, a smart speaker based diaphragmatic breathing monitoring system targeting early COPD stages I and II. BreathMentor is both unobtrusive and preventive of privacy invasion, so that it can solve the existing pain points and suits home care. BreathMentor converts the smart speaker into an active sonar system that continuously perceives and analyses the changes in surroundings, thereby detecting the user's respiration rate, deriving the breathing phases, and classifying whether the patient is practising diaphragmatic breathing. BreathMentor formulates breathing monitoring as a Temporal Action Localization task that enables us to detect each breathing cycle and classify its type. Our key insight is that breathing periodicity and phase duration are natural properties to localize and segment the breaths. Our key design to classify the breathing type is a hybrid architecture encompassing signal processing and deep learning techniques. Further, we evaluate the system performance on fifteen healthy subjects who would not breathe abnormally during diaphragmatic breathing under the supervision of therapists. In conclusion, BreathMentor can achieve robust performance for monitoring diaphragmatic breathing in different environments, as demonstrated in the results. The median error rate of respiration detection is 0.2 BPM, and the I/E ratio derivation is accurate with a mean absolute percentage error of less than 5.9% for breathing phase detection, together with a recall of 98.2%, and a precision of 95.5% in detecting diaphragmatic breathing. Above results indicate that BreathMentor can be used to track the patients' adherence and help monitor their breathing capacity.
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Crotti, C., F. Bartoli, M. Manara, P. A. Daolio, F. Zucchi, R. Caporali, L. Sinigaglia, and M. Varenna. "THU0421 TUMOR-INDUCED OSTEOMALACIA: DATA FROM A MONOCENTRIC EXPERIENCE ON 16 PATIENTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 448.2–449. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4486.
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Background:Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to a phosphaturic tumor, which overproduces fibroblast growth factor-23 (FGF-23), causing hyperphosphaturia, hypophosphoremia, low 1,25(OH)2VitD3and osteomalacia. Locating the tumor is critical, because lesions are typically small, benign mesenchymal tumors, anywhere in the body; the delay between onset of symptoms and diagnosis ranges from 2.5–28 years. Surgical removal is the only effective therapeutic approach.Objectives:To retrospectively evaluate patients affected by TIO, investigating clinical management and disease outcome.Methods:We retrospectively collected data of patients affected by TIO referred to a tertiary Rheumatology Center between Sep 2000 and Jan 2020.Results:We included 16 patients with a definite diagnosis of TIO, mean age±standard deviation 62.4±14.6 yrs, 56.2% females, mean age at symptoms onset 48.0±14.3 yrs (53.8±13.1 at diagnosis). Mean diagnostic delay between symptoms onset and tumor detection was 6.8±6.4 yrs. All patients complained bone pain, muscle weakness, and fractures before diagnosis of TIO. Biochemical findings were: mean serum Phosphorus (PS) 1.4±0.4 mg/dL (reference range (RR) 2.5-4.6), mean serum Calcium 9.4±0.7 mg/dL (RR 8.4-10.2), mean serum 1,25(OH)2VitD330.5±23.4 ng/L (RR 25-86). Intact-FGF-23 was dosed in 9 patients, always resulting elevated: mean 396.6±707.3 pg/mL (RR 25-45). PTH was increased in 30% of cases, while serum alkaline phosphatase was increased in 87.5%. 24h-Urine Phosphorus (PU) was increased in only 13% of patients, but, when renal phosphate wasting by tubular reabsorption of phosphate (TRP) was calculated, PU resulted increased in all.Tumor was localized in all cases (Fig.1) and were localized in bone and soft tissue, by using functional imaging, followed by anatomical techniques. Before the introduction in routinely practice of68Ga-DOTATATE-PET-CT in 2013, Octreoscan-SPECT/CT and18F FDG-PET were used as imaging modalities. Since 2013, diagnostic delay consistently reduced, from 8.6±8.3 yrs (7 patients) to 4.5±2.6 yrs (9 patients), confirming higher diagnostic accuracy of68Ga-DOTATATE-PET-CT.Figure 1.13 patients underwent surgery; in two cases surgery was not possible due to tumor location, so pharmacological support with phosphate supplements and calcitriol was started; a patient underwent to TC-guided radiofrequency ablation. After surgery, 7 patients experienced a complete remission, 3 had a persistence of the disease, and 3 an overtime relapse, even after a longstanding normalization of PS (6 years). After surgical tumor removal, PS significantly increased in few days (from 1.36±0.39 to 2.9±1.1, p=0.0001), while iFGF-23 levels tended to rapidly decreased (from 396.6±707.3 to 62.8±78.4). Before the introduction of68Ga-DOTATATE-PET-CT, 6 patients underwent to imaging-guided closed biopsy to confirm tumor localization; by using68Ga-DOTATATE-PET-CT only 2 subjects had closed biopsy. Furthermore, in our population only patients who had biopsy to detect the lesion (7 patients) had relapses compared to patients who did not.Conclusion:To our knowledge, this is the widest European cohort of patients affected by TIO reported in the last two decades. We confirm an important delay between symptoms onset and diagnosis. To locate tumor, a stepwise approach is recommended, starting with a thorough medical history and physical examination, followed by functional imaging, preferring68Ga-DOTATATE-PET-CT. Tumor biopsy is not recommended due to the potential cell spilling. Surgery is considered the only definitive treatment, aiming to a wider excision. Active surveillance is always needed, due to the possible relapses, even after a long period of complete clinical and biochemical remission.Disclosure of Interests: :Chiara Crotti: None declared, Francesca Bartoli: None declared, Maria Manara Consultant of: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Speakers bureau: Consultant and/or speaker for Eli-Lilly, MSD, Sanofi-Genzyme, Novartis, Alfa Wasserman and Cellgene, Primo Andrea Daolio: None declared, Francesca Zucchi: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Luigi Sinigaglia: None declared, Massimo Varenna: None declared
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Sunshine, Jacob. "Smart Speakers: The Next Frontier in mHealth." JMIR mHealth and uHealth 10, no. 2 (February 21, 2022): e28686. http://dx.doi.org/10.2196/28686.
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The rapid dissemination and adoption of smart speakers has enabled substantial opportunities to improve human health. Just as the introduction of the mobile phone led to considerable health innovation, smart speaker computing systems carry several unique advantages that have the potential to catalyze new fields of health research, particularly in out-of-hospital environments. The recent rise and ubiquity of these smart computing systems holds significant potential for enhancing chronic disease management, enabling passive identification of unwitnessed medical emergencies, detecting subtle changes in human behavior and cognition, limiting isolation, and potentially allowing widespread, passive, remote monitoring of respiratory diseases that impact public health. There are 3 broad mechanisms for how a smart speaker can interact with a person to improve health. These include (1) as an intelligent conversational agent, (2) as a passive identifier of medically relevant diagnostic sounds, and (3) by active sensing using the device's internal hardware to measure physiologic parameters, such as with active sonar, radar, or computer vision. Each of these different modalities has specific clinical use cases, all of which need to be balanced against potential privacy concerns, equity concerns related to system access, and regulatory frameworks which have not yet been developed for this unique type of passive data collection.
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Michez, Adrien, Stéphane Broset, and Philippe Lejeune. "Ears in the Sky: Potential of Drones for the Bioacoustic Monitoring of Birds and Bats." Drones 5, no. 1 (January 26, 2021): 9. http://dx.doi.org/10.3390/drones5010009.
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In the context of global biodiversity loss, wildlife population monitoring is a major challenge. Some innovative techniques such as the use of drones—also called unmanned aerial vehicle/system (UAV/UAS)—offer promising opportunities. The potential of UAS-based wildlife census using high-resolution imagery is now well established for terrestrial mammals or birds that can be seen on images. Nevertheless, the ability of UASs to detect non-conspicuous species, such as small birds below the forest canopy, remains an open question. This issue can be solved with bioacoustics for acoustically active species such as bats and birds. In this context, UASs represent an interesting solution that could be deployed on a larger scale, at lower risk for the operator, and over hard-to-reach locations, such as forest canopies or complex topographies, when compared with traditional protocols (fixed location recorders placed or handled by human operators). In this context, this study proposes a methodological framework to assess the potential of UASs in bioacoustic surveys for birds and bats, using low-cost audible and ultrasound recorders mounted on a low-cost quadcopter UAS (DJI Phantom 3 Pro). The proposed methodological workflow can be straightforwardly replicated in other contexts to test the impact of other UAS bioacoustic recording platforms in relation to the targeted species and the specific UAS design. This protocol allows one to evaluate the sensitivity of UAS approaches through the estimate of the effective detection radius for the different species investigated at several flight heights. The results of this study suggest a strong potential for the bioacoustic monitoring of birds but are more contrasted for bat recordings, mainly due to quadcopter noise (i.e., electronic speed controller (ESC) noise) but also, in a certain manner, to the experimental design (use of a directional speaker with limited call intensity). Technical developments, such as the use of a winch to safely extent the distance between the UAS and the recorder during UAS sound recordings or the development of an innovative platform, such as a plane–blimp hybrid UAS, should make it possible to solve these issues.
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Gottfredsson, Magnus, Thorarinn Tyrfingsson, Valgerdur Runarsdottir, Ottar M. Bergmann, Einar S. Bjornsson, Birgir Johannsson, Bryndis Sigurdardottir, et al. "Treatment as Prevention for Hepatitis C (TraP HepC). A Real-world Experience from the First 12 Months of a Nationwide Elimination Program in Iceland." Open Forum Infectious Diseases 4, suppl_1 (2017): S42. http://dx.doi.org/10.1093/ofid/ofx162.101.
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Abstract Background Hepatitis C virus (HCV) infection is associated with significant morbidity and mortality. Iceland, an island with a population of 330,000 has a HCV seroprevalence of 0.3% and an estimated total of 800–1000 patients. There is good access to health care among people who inject drugs (PWID) and Iceland thus serves as an ideal setting for a proof of concept intervention, aiming for elimination of the disease as a public health threat. If elimination is to be achieved PWID, who are key drivers of transmission, need to be a focus of treatment scale up. Methods All patients in the country infected with HCV were offered direct-acting antiviral agents (DAAs) starting in 01/2016. The regimens are chosen according to national guidelines; SOF/LDV +/−RBV through October 2016 and SOF/VEL +/− RBV thereafter. People with recent injection drug use (IDU), prisoners and patients with advanced liver disease are prioritized. PWID receive additional support to facilitate compliance. Various strategies are employed to enhance case detection and harm reduction. The goal is to initiate treatment for every patient in Iceland within 36 months (end-2018), aiming for elimination of domestic transmission of HCV. Results Twelve months after launching the nationwide program 527 patients had been evaluated, 53–66% of the estimated total patient population. The mean age is 42 years (range, 17–70 years, 2 males to every female). The reported main route of infection was IDU (90%). At the time of evaluation, 33% reported recent (within 6 months) IDU, 6% were homeless, and 5% in prison. Stimulants were the preferred IV drug among 84% of PWID but opiates by only 14%; overall 15% were receiving opiate substitution therapy (OST). During the first 12 months of the study period treatment with DAAs was initiated in 480 patients and 322 were scheduled to complete protocol. Drop-out rate is 6.5%. Sustained virological response at 12 weeks (SVR12) for the entire group, including patients who dropped out or are lost to follow-up is 90%. It is significantly lower among the homeless (60%) and active IDU (83% vs. 93%, P = 0.007). Conclusion A relatively large proportion of HCV infected patients in the community, including people actively injecting drugs, can be initiated on treatment in a short period of time. Current drug use does not preclude treatment success. Disclosures M. Gottfredsson, Gilead: Grant Investigator and Scientific Advisor, Consulting fee and Research support; Astellas: Consultant, Speaker honorarium
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Zheng, Hong-Ying, Gang Peng, Jian-Yong Chen, Caicai Zhang, James W. Minett, and William S.-Y. Wang. "The Influence of Tone Inventory on ERP without Focal Attention: A Cross-Language Study." Computational and Mathematical Methods in Medicine 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/961563.
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This study investigates the effect of tone inventories on brain activities underlying pitch without focal attention. We find that the electrophysiological responses to across-category stimuli are larger than those to within-category stimuli when the pitch contours are superimposed on nonspeech stimuli; however, there is no electrophysiological response difference associated with category status in speech stimuli. Moreover, this category effect in nonspeech stimuli is stronger for Cantonese speakers. Results of previous and present studies lead us to conclude that brain activities to the same native lexical tone contrasts are modulated by speakers’ language experiences not only in active phonological processing but also in automatic feature detection without focal attention. In contrast to the condition with focal attention, where phonological processing is stronger for speech stimuli, the feature detection (pitch contours in this study) without focal attention as shaped by language background is superior in relatively regular stimuli, that is, the nonspeech stimuli. The results suggest that Cantonese listeners outperform Mandarin listeners in automatic detection of pitch features because of the denser Cantonese tone system.
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Numan, Yazan, Zaid Abdel Rahman, Justin Grenet, Stephanie Boisclair, Jan Philipp Bewersdorf, Dylan Barth, Amer M. Zeidan, et al. "Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors." Blood 136, Supplement 1 (November 5, 2020): 5–7. http://dx.doi.org/10.1182/blood-2020-137251.
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Background: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) AML and FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) enrolled prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3inhibitor (FLT3i) maintenance. Some mechanisms of drug resistance can be shared across FLT3i's, suggesting response to gilteritinib might differ in patients treated with frontline FLT3i. A better understanding of how prior therapy modulates response to gilteritinib is necessary to clarify this novel agent's role in the current FLT3-mutated AML treatment algorithm. Methods: This is an ongoing multi-institutional analysis from 13 US centers identifying patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. Patients who received gilteritinib as a part of an ongoing trial were excluded. Response criteria were identical to the ADMIRAL trial. For patients with available data and a composite complete remission (CRc), we defined clinically measurable residual disease (cMRD) negative status by bone marrow flow cytometry using a cutoff of <1 x 10x105 cells as well as polymerase chain reaction (PCR) for FLT3 mutation with a minimum sensitivity of 5%. Survival from the time of gilteritinib initiation was recorded. Multivariate analysis included all variables collected to determine interaction with patient outcome (CR and survival data). Kaplan-Meier curves and log rank test were used for survival analysis after gilteritinib initiation. Results: 72 patients treated with prior FLT3i exposure received gilteritinib for treatment of R/R FLT3mut+ AML. Patient characteristics are presented in table-1 with 46 (64%) previously receiving midostaurin, 19 (26%) sorafenib, and 7 (10%) other FLT3i. 8 (11%) received more than one prior TKI. NGS at diagnosis were available in 66 patients (92%) and co-mutations in DNMT3A, NPM1 and NRAS were observed in more than 10% of patients. Average duration of gilteritinib therapy was 5.7 months (range: 0.2-25 months). 27 (37.5%) received stem cell transplant (SCT) before gilteritinib and 15 (21%) underwent SCT after gilteritinib. The composite CR rate (CRc, defined as CR + CRi + CRp) was 51.4% (n= 37 patients). With regard to specific FLT3i's, we found no significant difference in median survival (7.1 months and 6.4 months for midostaurin and sorafenib, respectively) or remission rates (CRc 54% and 47% for prior midostaurin and sorafenib, respectively). The CRc rate for patients who received only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. A trend toward higher CRc rate was noted in patients treated with gilteritinib in combination regimens rather than as a single agent (64% vs 43%, respectively, p=0.09 using Chi-square test). No survival advantage for combination therapy was seen over single agent. Survival was longest in patients who obtained a CR, particularly a cMRD negative response; this remained significant after censoring at the time of SCT (figures 1&2). Patients who received SCT after gilteritinib had significantly longer survival than non-transplanted patients (9.3 months vs 5.6 months, respectively, HR 0.44, 95% CI 0.2-0.8)(figure-3). Patients with concurrent mutations of NPM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival. With regard to mutations associated with drug resistance to other FLT3i's, patients with both FLT3-ITD and FLT3-D835 mutation had similar response and survival to FLT3-ITD alone. However, patients with MAPK pathway activating mutations (e.g. NRAS and PTPN11) had lower CRc (37.5% vs 59.5%) and poorer median survival than other patients (3.3 months vs 7.5 months) (HR 2.2- 95% CI 1.1-4.4) p value <0.01(figure-4). Conclusions: In this multi-center, retrospective analysis, gilteritinib remains a clinically active agent after treatment failure of prior FLT3i's (midostaurin or sorafenib). Mutations activating MAPK pathway have been implicated in secondary gilteritinib resistance but are seldom co-mutated at initial FLT3mut+ AML diagnosis. While further study is required, we hypothesize that their detection after frontline FLT3i therapy may represent treatment-emergent clones with propensity for pan-FLT3i resistance. Disclosures Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; MedImmune/Astrazeneca: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Daver:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perl:Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Biomed Valley Discoveries: Research Funding; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Syndax: Consultancy, Honoraria; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; New Link Genetics: Honoraria, Other; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; Takeda: Honoraria, Other: Travel costs for meeting. Altman:Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; PeerView: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; Fujifilm: Research Funding. OffLabel Disclosure: Some of the patients we are reporting on received gilteritinib in combination with other agents which is off-label use.
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Volkova, Svitlana, and Eric Bell. "Identifying Effective Signals to Predict Deleted and Suspended Accounts on Twitter Across Languages." Proceedings of the International AAAI Conference on Web and Social Media 11, no. 1 (May 3, 2017): 290–98. http://dx.doi.org/10.1609/icwsm.v11i1.14874.
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Social networks have an ephemerality to them where accounts and messages are constantly being edited, deleted, or marked as private. This continuous change comes from concerns around privacy, a potential desire for to be forgotten and suspicious behavior. In this study we present a novel task – predicting suspicious e.g., to be deleted or suspended accounts in social media. We analyze multiple datasets of thousands of active, deleted and suspended Twitter accounts to produce a series of predictive representations for the removal or shutdown of an account. We selected these accounts from speakers of three languages – Russian, Spanish, and English to evaluate if speakers of various languages behave differently with regards to deleting accounts. We compared the predictive power of the state-of-the-art machine learning models to recurrent neutral networks trained on previously unexplored features. Furthermore, this work is the first to rely on image and affect signals in addition to language and network to predict deleted and suspended accounts in social media. We found that unlike widely used profile and network features, the discourse of deleted or suspended versus active accounts forms the basis for highly accurate account deletion and suspension prediction. More precisely, we observed that the presence of certain terms in tweets leads to a higher likelihood for that user’s account deletion or suspension. Moreover, despite image and affect signals yield lower predictive performance compared to language, they reveal interesting behavioral differences across speakers of different languages. Our extensive analysis and novel findings on language use and suspicious behavior of speakers of different languages can improve the existing approaches to credibility analysis, disinformation and deception detection in social media.
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Coyne, Joseph T., and Mark D. Lee. "The Effects of Visual Cues and Interstimulus Interval on Accuracy in Auditory Localization and Detection." Proceedings of the Human Factors and Ergonomics Society Annual Meeting 46, no. 17 (September 2002): 1613–17. http://dx.doi.org/10.1177/154193120204601718.
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Auditory localization is an increasingly important topic as the technology for audio displays is becoming more available. However, few studies examine the effects of multiple simultaneous distracters on auditory detection and localization performance. Previous research has found that detection and localization performance significantly drop as the number of distracters increases; however, it is not clear what causes these errors. In the present study, participants either had to localize an auditory stimulus or detect an auditory stimulus among multiple distracters. Similar to previous research the number of errors significantly increased as the number of active speakers increased. Also consistent with previous research, the detection performance was better than the localization performance. The use of visual cues was found to benefit the localization group but did not significantly affect performance in the detection group. The present study also found that a longer interstimulus interval improved accuracy only in the localization group, and then only when visual cues were present. These findings provide insight into the complex nature of the auditory search task.
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Gish, Robert, and Vincent Streva. "1066. Immune Escape Mutant Detection Using Commercially Available Methods for Hepatitis B Surface Antigen Serological Testing." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S562. http://dx.doi.org/10.1093/ofid/ofaa439.1252.
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Abstract Background Although overall infection rates of Hepatitis B virus (HBV) in the United States (US) remain stable, as many as 2.2 million persons are still chronically infected with Hepatitis B Virus (HBV)1. Persons who inject drugs (PWID) are at a higher risk of HBV infection and since 2009 three states (KY, TN, WV) have reported up to a 114% increase in cases of acute HBV infection due to higher infection rates among a non-Hispanic white populations (30–39 years), and injection drug users2. Hepatitis B vaccination is recommended as primary prevention for adults who are at increased risk for HBV infection, including PWID. However, data from the National Health Interview Survey indicate that hepatitis B vaccination coverage is low among adults in the general population3, and it is likely to be lower among injection drug users. Hepatitis B Surface Antigen (HBsAg) is the first serological marker to appear after HBV exposure and infection; this marker is included in the recommended panel for acute hepatitis diagnosis and accurate detection is necessary for early and accurate diagnosis. Serological testing challenges exist for HBsAg due to the high degree of genetic variability which can further be exacerbated by endogenous and exogenous pressures. The immuno-dominant region may have one or more mutations described as immune escape mutations which can decrease or abrogate HBsAg binding to antibodies used in immunoassays. Although the prevalence of these mutations is not well documented in the United States, international studies have shown that up to 79% of HBV-reactivated patients (vs 3.1% of control patients; p< 0.001) carry HBsAg mutations localized in immune-active HBsAg regions4. Methods A study was conducted using a panel of 10 unique recombinant HBsAg immune escape mutants. Panel members were tested by commercially available HBsAg serological immunoassays. Results It was found that although commercially available HBsAg immunoassays are the primary diagnostic tool for HBV diagnosis, not all HBsAg immune escape mutants are detected, with some method detecting as few as 5 out of 10 of these mutant samples. Figure 1 Conclusion Improvement is needed in commercially available methods for the accurate detection of HBsAg. Disclosures Robert Gish, MD, Abbott (Consultant)AbbVie (Consultant, Advisor or Review Panel member, Speaker’s Bureau)Access Biologicals (Consultant)Antios (Consultant)Arrowhead (Consultant)Bayer (Consultant, Speaker’s Bureau)Bristol Myers (Consultant, Speaker’s Bureau)Dova (Consultant, Speaker’s Bureau)Dynavax (Consultant)Eiger (Consultant, Advisor or Review Panel member)Eisai (Consultant, Speaker’s Bureau)Enyo (Consultant)eStudySite (Consultant, Advisor or Review Panel member)Exelixis (Consultant)Fujifilm/Wako (Consultant)Genentech (Consultant)Genlantis (Consultant)Gilead (Consultant, Advisor or Review Panel member, Speaker’s Bureau)GLG (Consultant)HepaTX (Consultant, Advisor or Review Panel member)HepQuant (Consultant, Advisor or Review Panel member)Intercept (Consultant, Speaker’s Bureau)Ionis (Consultant)Janssen (Consultant)Laboratory for Advanced Medicine (Consultant)Lilly (Consultant)Merck (Consultant)Salix (Consultant, Speaker’s Bureau)Shionogi (Consultant, Speaker’s Bureau)Viking (Consultant)
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Maksymowych, W. P., S. Juhl Pedersen, U. Weber, P. M. Machado, X. Baraliakos, J. Sieper, S. Wichuk, et al. "FRI0302 WHAT IS THE IMPACT OF DISCREPANCY BETWEEN CENTRAL AND LOCAL READERS IN EVALUATION OF MRI SCANS ON THE CLASSIFICATION OF AXIAL SPONDYLOARTHRITIS? DATA FROM THE ASAS CLASSIFICATION COHORT STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 740.2–741. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6350.
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Background:Active MRI lesions typical of axial spondyloarthritis (axSpA) were reported in 61.6% and 2.2% of axSpA and not-axSpA patients, respectively, from the ASAS classification cohort (ASAS-CC)1. Discrepancy between local and central reader evaluation of MRI scans could result in differences in numbers of patients fulfilling the imaging arm of the ASAS classification criteria. But final classification may not be impacted if discrepant patients still fulfill the clinical arm.Objectives:We aimed to assess the impact of reader discrepancy in detection of active MRI lesions on the number of patients classified as having axSpA in patients recruited to the ASAS-CC.Methods:MRI images of the sacroiliac joints (SIJs) were available from 252 cases in the ASAS-CC, and these also had clinical and radiographic data. Seven central readers from the ASAS-MRI group recorded MRI lesions in an eCRF that included active lesions typical of axSpA in the SIJ (MRI-active) that was worded exactly the same as in the original ASAS-CC eCRF permitting comparisons between central and local site readers. Active lesions were deemed to be present according to majority agreement (≥4/7) of central readers and also any 2 central readers. We calculated the number of patients that were classified differently after central evaluation for overall fulfilment of the ASAS criteria and for the imaging arm.Results:Discordance between central and local readers for detection of MRI-active was recorded in 45(17.8%) and 47(18.2%) of cases according to 2-reader and majority (≥4/7) central reader data, respectively (kappa (95%CI) of 0.64 (0.54-0.73) and 0.62 (0.53-0.72). With central reading as external standard the false-positive rate for active lesions was 26.9%% and 32.2% (‘local overcall’) for 2-reader and majority reader data, respectively. There were 159(63.1%) patients who fulfilled the ASAS axSpA criteria based on local-reading, and 148(58.7%) and 143(56.7%) patients based on 2-reader and majority central-reading, respectively (Table). When fulfillment of the imaging arm was the primary consideration (irrespective of the clinical arm), 126 (50%) patients fulfilled the criteria based on local-reading, and 111 (44%) and 102 (40.5%) patients based on 2-reader and majority central-reading, respectively.Conclusion:Despite substantial overcall for positive MRI SIJ inflammation by local readers, the number of patients classified as having axSpA did not change substantially. This is due to the alternate mechanism for classification through the clinical arm.References:[1]Rudwaleit et al. Ann Rheum Dis 2009;68: 777-83Impact of Central Vs. Local Reader SIJ MRI Inflammation Assessment on SpA Classification in cases with all clinical, radiographic, and central and local MRI inflammation data available (n=252)MRI assessment usedSpA Classification = Yes N(%)SpA Classification = No N(%)Imaging Arm SpA Classification = Yes N(%)Imaging Arm SpA Classification = No N(%)Local Reader MRI positive159 (63.1%)93 (36.9%)126 (50%)126 (50%)>2 Central Reader MRI positive148 (58.7%)104 (41.3%)111 (44.0%)141 (56.0%)Majority Central Reader (≥4/7) MRI positive143 (56.7%)109 (43.2%)102 (40.5%)150 (59.5%)Disclosure of Interests:Walter P. Maksymowych Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Speakers bureau: AbbVie, Janssen, Novartis, Pfizer, and UCB, Susanne Juhl Pedersen Grant/research support from: Novartis, Ulrich Weber: None declared, Pedro M Machado Consultant of: PMM: Abbvie, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Speakers bureau: PMM: Abbvie, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Joachim Sieper Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Stephanie Wichuk: None declared, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Martin Rudwaleit Consultant of: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Joel Paschke: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Robert G Lambert: None declared
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Bocchia, Monica, Lara Aprile, Santina Sirianni, Elisabetta Abruzzese, Antonella Gozzini, Fausto Castagnetti, Luca Puccetti, et al. "Peripheral Blood Flow-Cytometry Chronic Myeloid Leukemia Stem Cells Detection and Quantification during Tyrosine Kinase Inhibitors Therapy." Blood 128, no. 22 (December 2, 2016): 942. http://dx.doi.org/10.1182/blood.v128.22.942.942.
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Abstract Introduction: In chronic myeloid leukemia (CML), tyrosine Kinase Inhibitors (TKIs) treatment is a potentially life-time therapy for the majority of patients (pts), as few of them, only after achieving a deep and stable molecular response, may discontinue TKIs without recurrence of disease. Available data suggest that relapse after TKIs discontinuation is due to the persistence of leukemic stem cells (LSCs) intrinsically resistant to TKIs. Survival of CML LSCs may be the consequence of activation of several pathways BCR-ABL1 independent. qRT-PCR, the most sensitive assay to monitor disease status in CML pts, may be inappropriate to quantify residual quiescent CML LSCs that are transcriptionally silent. Therefore, the possibility to easily quantify LSCs during TKIs treatment is a great opportunity to better understand the behavior of residual LSCs and potentially to identify those pts candidates to safely discontinue TKIs. Recently, Valent et al described that CD34+/CD38-/Lin- CML LSCs specifically co-express dipeptidylpeptidase IV (CD26) and that CD26 is a potential biomarker for the quantification and isolation of CML LSCs, in bone marrow samples of CML patients. Furthermore, Culen et al. quantified CD26+ LSCs bone marrow compartment in 31 CML patients at diagnosis and their number appears to correlate with response to TKIs treatment. In the present study we wanted to explore the feasibility, rate and potential implication of detecting CD26+ LSCs in peripheral blood (PB) from CML pts during TKI treatment. Methods: CML pts during first line treatment with any approved TKIs, referring to several Italian Hematology Centers, entered this non interventional cross sectional study after signing a proper informed consent. During a routine follow up visit, in which pts were checked for molecular response by standard PB qRT-PCR BCR-ABL1 analysis, additional 3 mls of PB were collected in EDTA and sent within 24 hours to Siena Hematology Lab to detect CD34+/CD38-/CD26+ LSCs by multicolor flow cytometry. After red blood cells lysis, cells were incubated with anti CD45 (BD Biosciences), CD34 (581), CD38 (HIT2), CD26 (M-A261) (BD Pharmigen). After washing, acquisition and analysis were performed by FACSCanto II (BD Biosciences, NR Nannini) using DIVA 8 software (BD, Biosciences). CD45+ cells acquired for each sample ranged from 500,000 to 1,000,000. Isotype controls were included in each staining. In 5 pts a FISH analysis of PB sorted CML LSCs population was also performed. Results: to validate our assay we first performed a FISH analysis of both PB sorted CD34+/CD38-/CD26+ and CD34+/CD38-/CD26- in 5 CML patients at 3-6 months after starting treatment, confirming Ph+ cells only in the CD26+ fraction. Afterward, we checked for circulating CML LSCs a total of 202 CML pts in first line treatment with TKIs for a median of 39 months (range 1-175). Type of TKI, length of treatment, molecular response and quantification of LSCs are summarized in Table 1. PB CML LSCs were detectable in 146/202 (72.3%) pts with a median number of CD26+ of 0,0165 cells/µL (range 0,0018-0,66). Kendall rank correlation coefficient used to analyze the relation between the measurable variables showed no correlation between BCR-ABL/ABLIS ratio (median 0,004 range 0-61) and number of residual LSCs (r 0.118 p=0.097). In 56/202 (27.7%) pts CD26+ LSCs were undetectable, yet we found no correlation with the concomitant degree of molecular response. Conclusions: this study represents the first attempt to measure in a large cohort of CML patients residual circulating LSCs during TKIs treatment. In our hands PB LSCs flow-cytometry assay appeared feasible, specific and sensitive and thus suitable for routine monitoring. As expected, the majority of CML patients, even in deep molecular response, still harbor residual LSCs and the number of PB CD26+ did not correlate with the number of BCR-ABL1 copies. This evidence suggests that the molecular response refers to transcriptionally active CML progenitor cells and not to quiescent, TKIs resistant, CML LSCs. Prospective studies evaluating the behavior of PB CML LSCs during different TKIs treatment, as well as studies monitoring PB CD26+ in CML pts that discontinued TKIs treatment are ongoing. Our goal is to rule out the impact, if any, of a "stem cell response" in addition to the standard molecular response in the management of CML patients mainly to identify those pts candidates for a safe TKI discontinuation. Disclosures Bocchia: Janssen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Aprile:Novartis: Honoraria. Castagnetti:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.
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Lambert, R., X. Baraliakos, S. Bernard, J. Carrino, T. Diekhoff, I. Eshed, K. G. Hermann, et al. "POS0989 DEVELOPMENT OF INTERNATIONAL CONSENSUS ON A STANDARDIZED IMAGE ACQUISITION PROTOCOL FOR DIAGNOSTIC EVALUATION OF THE SACROILIAC JOINTS BY MRI – AN ASAS-SPARTAN COLLABORATION." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 802.3–803. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3365.
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BackgroundIn 2009, ASAS published a ‘Definition of active sacroiliitis on MRI for classification of axial spondyloarthritis (axSpA)’. This definition relied on two MRI sequences to make this determination – semicoronal T1 and STIR. Since then, this approach has frequently been used for diagnosis, even though that was never the intent of the definition. In 2015, the European Society of Skeletal Radiology (ESSR) published its recommendations for an SIJ MRI image acquisition protocol (IAP) for diagnostic purposes that required 4 MRI sequences but there is still no IAP that has been widely accepted as a minimum standard worldwide. In 2020, an informal survey of 24 academic sites (12 Europe, 12 North America) confirmed that 24/24 sites performed a minimum of 3 MRI sequences for diagnosis (19 performed 4-8 sequences) because the 2-sequence protocol was considered inadequate.ObjectivesTo develop the minimum requirements for a standardized IAP for MRI of the sacroiliac joints for diagnostic ascertainment of sacroiliitis.MethodsAll radiologist members of the ASAS and SPARTAN Classification in axSpA (CLASSIC) project, along with one European and one North American rheumatologist with extensive MRI experience in SpA clinical practice and research, were invited to participate in a consensus exercise. A draft IAP was circulated to all participants along with background information and justification for the draft proposal. Feedback on all issues was received by email, tabulated and recirculated. Participants were broadly in favour of the proposal and two months later a teleconference meeting took place and remaining points of contention were resolved. Examples of the proposed IAP performed on new, 10 and 22 years’ old MRI scanners were made available for review in DICOM format. Next the revised draft of the IAP was presented at the ASAS annual meeting to the entire membership on 14 January 2022, and voted on.ResultsA 4-sequence IAP, 3-semicoronal and 1-semiaxial, is recommended for diagnostic ascertainment of sacroiliitis and its differential diagnoses (Table 1). It must meet the following requirements: Semicoronal sequences should be parallel to the dorsal cortex of the S2 vertebral body, and include: 1) a sequence sensitive for the detection of active inflammation being T2-weighted with suppression of fat signal; 2) a sequence sensitive for the detection of structural damage in bone and bone marrow with T1-weighting; 3) a sequence that is designed to optimally depict the bone-cartilage interface of the articular surface and be sensitive for detection of bone erosion; plus 4) a semiaxial sequence sensitive for inflammation detection. The IAP was approved at the ASAS annual meeting by a vote of the entire membership with 91% in favour.Table 1.A standardized SIJ MRI Acquisition Protocol for diagnostic ascertainment of sacroiliitisOrientationSequenceTarget Lesion(s)Semicoronal Parallel to the dorsal cortex of the S2 vertebral bodyT1-weighted Spin EchoStructural: Fat lesions, erosion, sclerosis, backfill, ankylosis.T2-weighted with suppressed fat signal (STIR, T2FS or equivalent)Inflammatory: Bone marrow edema (BME)T1-weighted with suppressed fat signal (2D or 3D T1FS)Structural: Erosion of the articular surfaceSemiaxial Perpendicular to semicoronalT2-weighted with suppressed fat signal (STIR, T2FS or equivalent)Inflammatory: Bone marrow edema (BME)ConclusionA standardized IAP for MRI of the sacroiliac joints for diagnostic ascertainment of sacroiliitis is recommended and should be comprised of a minimum of 4 sequences, in 2-planes, that will optimally visualize inflammation, structural damage, and the bone-cartilage interface.Disclosure of InterestsRobert Lambert Paid instructor for: Novartis, Consultant of: Calyx, CARE Arthritis, Image Analysis Group, Xenofon Baraliakos Speakers bureau: Abbvie, Pfizer, MSD, UCB, Novartis, Lilly, Galapagos, Hexal, Paid instructor for: Abbvie, Pfizer, MSD, UCB, Novartis, Lilly, Galapagos, Hexal, Consultant of: Abbvie, Pfizer, MSD, UCB, Novartis, Lilly, Galapagos, Hexal, Grant/research support from: Abbvie, MSD, Novartis, Lilly, Stephanie Bernard Consultant of: Elsevier Amirsys, John Carrino Consultant of: Pfizer, Regeneron, Globus, Carestream, Image Analysis Group, Image Biopsy Lab, Torsten Diekhoff Speakers bureau: Novartis, MSD, Canon MS, Consultant of: Eli Lilly, Iris Eshed: None declared, Kay-Geert Hermann Speakers bureau: AbbVie, Pfizer, MSD, Novartis. Co-founder: BerlinFlame GmbH, Nele Herregods: None declared, Jacob L Jaremko: None declared, Lennart Jans: None declared, Anne Grethe Jurik: None declared, John O’Neill: None declared, Monique Reijnierse: None declared, Michael Tuite Consultant of: GE HealthCare, Walter P Maksymowych Speakers bureau: Abbvie, Janssen, Novartis, Pfizer, UCB, Consultant of: Abbvie, Boehringer Ingelheim, Celgene, Eli-Lilly, Galapagos, Novartis, Pfizer, UCB, Grant/research support from: Abbvie, Novartis, Pfizer, UCB
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Deshpande, Pushkar, Christian Brandt, Stefan Debener, and Tobias Neher. "Comparing Clinically Applicable Behavioral and Electrophysiological Measures of Speech Detection, Discrimination, and Comprehension." Trends in Hearing 26 (January 2022): 233121652211397. http://dx.doi.org/10.1177/23312165221139733.
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Effective communication requires good speech perception abilities. Speech perception can be assessed with behavioral and electrophysiological methods. Relating these two types of measures to each other can provide a basis for new clinical tests. In audiological practice, speech detection and discrimination are routinely assessed, whereas comprehension-related aspects are ignored. The current study compared behavioral and electrophysiological measures of speech detection, discrimination, and comprehension. Thirty young normal-hearing native Danish speakers participated. All measurements were carried out with digits and stationary speech-shaped noise as the stimuli. The behavioral measures included speech detection thresholds (SDTs), speech recognition thresholds (SRTs), and speech comprehension scores (i.e., response times). For the electrophysiological measures, multichannel electroencephalography (EEG) recordings were performed. N100 and P300 responses were evoked using an active auditory oddball paradigm. N400 and Late Positive Complex (LPC) responses were evoked using a paradigm based on congruent and incongruent digit triplets, with the digits presented either all acoustically or first visually (digits 1–2) and then acoustically (digit 3). While no correlations between the SDTs and SRTs and the N100 and P300 responses were found, the response times were correlated with the EEG responses to the congruent and incongruent triplets. Furthermore, significant differences between the response times (but not EEG responses) obtained with auditory and visual-then-auditory stimulus presentation were observed. This pattern of results could reflect a faster recall mechanism when the first two digits are presented visually rather than acoustically. The visual-then-auditory condition may facilitate the assessment of comprehension-related processes in hard-of-hearing individuals.
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Blau, Olga, Franziska Behrenbeck, Mirgul Bayanova, Igor-Wolfgang Blau, and Lars Bullinger. "Characteristics of DNMT3A-R882 Mutation in AML." Blood 132, Supplement 1 (November 29, 2018): 5263. http://dx.doi.org/10.1182/blood-2018-99-116652.
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Abstract Introduction Genetic mutations play an important role in the development and progression of acute myeloid leukemia (AML). One of the common aberration in AML is mutation in the epigenetic modifying gene, DNA methyltransferase 3α (DNMT3A). Despite the active investigations, the exact impact of mutation on the development of AML is not completely known. The occurrence of mutation in pre-leukemic cells explains a particular attention to DNMT3A. The most common mutation is located in codon R882 (DNMT3AR882mut). The objective of this study is to compare clinical and prognostic characteristics of AML patients in relation to presence of DNMT3AR882mut. The quantification of the mutation burden in follow up samples was performed both after standard therapy and after allogeneic stem cell transplantation (alloSCT). In addition, it was investigated whether the quantification of the mutational burden of DNMT3AR882mut is significant to the progression of disease. Methods Samples of 580 AML were retrospective analyzed using HRM-PCR, capillare electrophorese, and Sanger Sequencing. The median observation period was 495 days. Of 580, 69 have DNMT3AR882mut. Mutation burden was evaluated in follow-up samples by quantitative PCR. The statistical methods were selected according to sample distribution and evaluated with SPSS (significance level p <0.05). Results DNMT3A R882mut were associated with a higher level of leukocytes and blasts at diagnosis, with M4-M5 variant of AML, and with normal karyotype. It was found that NPM1 and FLT3-ITD are more frequent co-mutations that have a significant effect on the prognosis of disease. Analysis of mutation burden of DNMT3AR882mut at diagnosis showed a large spread (0.02 - 66.9 %). At the time of diagnosis, DNMT3AR882mut transcript levels did not correlate with clinical and prognostic characteristics. The mutation burden decreased after therapy, but was always visible in CR after standard therapy. In CR after allogeneic stem cell transplantation (alloSCT) with complete donor chimerism mutation was not detected. In relapse of AML, an increasing of the mutation burden were found in all patients, both after therapy, and after alloSCT. In relapse samples, the same mutant clone was found. Conclusion The DNMT3A mutation is a common genetic aberration in AML patients, which is associated with specific clinical and prognostic data. The presence of co-mutations, especially NPM1 and FLT3-ITD, has a significant effect on the prognosis of patients. Quantitative detection of DNMT3AR882mut at different time points of disease revealed the persistence of mutated clone after standard therapy and disappearance of DNMT3AR882mut after alloSCT. It is suggest that alloSCT is the optimal treatment option for the eradication of DNMT3AR882mut in AML patients. Disclosures Bullinger: Sanofi: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Bayer Oncology: Research Funding.
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Sung, Jee Eun, Sujin Choi, Bora Eom, Jae Keun Yoo, and Jee Hyang Jeong. "Syntactic Complexity as a Linguistic Marker to Differentiate Mild Cognitive Impairment From Normal Aging." Journal of Speech, Language, and Hearing Research 63, no. 5 (May 22, 2020): 1416–29. http://dx.doi.org/10.1044/2020_jslhr-19-00335.
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Purpose In this study, we sought to identify critical linguistic markers that can differentiate sentence processing of individuals with mild cognitive impairment (MCI) from the sentence processing of normal-aging populations by manipulating sentences' linguistic complexity. We investigated whether passive sentences, as linguistically complex structures, can serve as linguistic markers that can contribute to diagnoses that distinguish MCI from normal aging. Method In total, 52 participants, including 26 adults with amnestic MCI and 26 cognitively unimpaired adults, participated in the study. All participants were native speakers of Korean. We administered the two subsets of active and passive conditions using a sentence–picture paradigm with semantically reversible sentences to both groups. Results A mixed-effects model using PROC NLMIXED demonstrated that the MCI group exhibited differentially greater difficulty in processing passive than active sentences compared to the normal-aging group. A logistic regression fitted with the PROC LOGISTIC model identified the sum of the passive sentences, with age and education effects as the best models to distinguish individuals with MCI from the normal-aging group. Conclusion Sentence comprehension deficits emerged in the MCI stage when the syntactic complexity was increased. Furthermore, a passive structure was the best predictor for efficiently distinguishing the MCI group from the normal-aging group. These results are clinically and theoretically important, given that linguistic complexity can serve as a critical behavioral marker in the detection of early symptoms associated with linguistic–cognitive decline.
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Amichai, Eran, Gaddi Blumrosen, and Yossi Yovel. "Calling louder and longer: how bats use biosonar under severe acoustic interference from other bats." Proceedings of the Royal Society B: Biological Sciences 282, no. 1821 (December 22, 2015): 20152064. http://dx.doi.org/10.1098/rspb.2015.2064.
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Active-sensing systems such as echolocation provide animals with distinct advantages in dark environments. For social animals, however, like many bat species, active sensing can present problems as well: when many individuals emit bio-sonar calls simultaneously, detecting and recognizing the faint echoes generated by one's own calls amid the general cacophony of the group becomes challenging. This problem is often termed ‘jamming’ and bats have been hypothesized to solve it by shifting the spectral content of their calls to decrease the overlap with the jamming signals. We tested bats’ response in situations of extreme interference, mimicking a high density of bats. We played-back bat echolocation calls from multiple speakers, to jam flying Pipistrellus kuhlii bats, simulating a naturally occurring situation of many bats flying in proximity. We examined behavioural and echolocation parameters during search phase and target approach. Under severe interference, bats emitted calls of higher intensity and longer duration, and called more often. Slight spectral shifts were observed but they did not decrease the spectral overlap with jamming signals. We also found that pre-existing inter-individual spectral differences could allow self-call recognition. Results suggest that the bats’ response aimed to increase the signal-to-noise ratio and not to avoid spectral overlap.
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Hay, Annette E., Sarit Assouline, Roland B. Walter, Richard F. Little, Anna Moseley, Sperling M. Gail, Annie Im, et al. "Accrual Barriers and Detection of Early Toxicity Signal in Older Less-Fit Patients Treated with Azacitidine and Nivolumab for Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS) in the SWOG 1612 Platform Randomized Phase II/III Clinical Trial." Blood 134, Supplement_1 (November 13, 2019): 3905. http://dx.doi.org/10.1182/blood-2019-124320.
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Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.
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Vikse, J., Ø. Midtvedt, Ø. Molberg, B. T. Svanes Fevang, Ø. Palm, T. Garen, K. B. Norheim, et al. "OP0255 IGG4-RELATED DISEASE ACTIVITY ASSESSMENT INFLUENCED BY USE OF 18F-FDG PET/CT: DATA FROM A NORWEGIAN COHORT." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 169.1–169. http://dx.doi.org/10.1136/annrheumdis-2023-eular.3560.
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BackgroundThe IgG4-related disease (IgG4-RD) responder index (RI) is a validated tool to assess disease activity in IgG4-RD [1]. The RI reflects symptoms attributable to active IgG4-RD as well as relevant findings from the physical examination, imaging and laboratory evaluations, with higher scores reflecting more active disease. Multiorgan involvement and higher RI scores were identified as risk factors for relapse [2], indicating a need for more aggressive treatment. Whole-body18F-FDG PET/CT is a sensitive technique for detecting foci of active inflammation, but its use is limited by cost and availability. Furthermore, whether18F-FDG PET/CT detects additional organ manifestations which influence RI and treatment decisions, is largely unknown.ObjectivesTo compare performance of a pure clinical RI model (c-RI) and a c-RI with addition of18F-FDG PET/CT (c-PET-RI) in a well-characterized Norwegian IgG4-RD cohort.MethodsAdult patients with IgG4-RD seen at the Oslo University Hospital were included if they had performed both18F-FDG PET/CT and a comprehensive assessment by a rheumatologist within a four-week interval. In each patient, we calculated c-RI from symptoms, clinical examination, and laboratory studies, and c-PET-RI from the c-RI plus the score from pathological18F-FDG organ uptake on the whole-body PET. Both indices were calculated using data from NOSVAR research registry and electronic medical records. We defined IgG4-RD disease activity as low if RI was ≤ 3 and high if RI was > 3 points. We assessed associations of elevated CRP and serum IgG4 (s-IgG4) with reclassification (discrepancy change in disease activity scores (c-PET-RI – c-RI)) by applying logistic regression with odds ratio (OR) and 95% CI to identify patients in which performing18F-FDG PET/CT is likely to change treatment decisions.ResultsThe study cohort included 53 IgG4-RD patients, of whom 30 had c-RI ≤ 3 points, consistent with low disease activity. In 15/30 patients (50%) with c-RI ≤ 3, the corresponding c-PET-RI was > 3 points, consistent with high disease activity. In these 15 patients, the mean increase in RI points from the18F-FDG PET/CT was 6.4 (range 2-12). We found that 14 of these 15 patients (93%) had elevated s-IgG4 and 6 (40%) had elevated CRP. In logistic regression analysis, elevated s-IgG4, but not CRP, was strongly associated with reclassification to high disease activity after18F-FDG PET/CT (OR 16.0, 95% CI 1.7-154.6, p = 0.017). Of the 9 patients with c-RI ≤ 3 and normal s-IgG4, only one (11%) was reclassified to high disease activity after18F-FDG PET/CT.ConclusionIn IgG4-RD patients with low disease activity by clinical and laboratory assessment (c-RI), elevated s-IgG4 is associated with detection of asymptomatic organ involvement by18F-FDG PET/CT (c-PET-RI). Hence, evaluation with18F-FDG PET/CT should be considered in patients with c-RI ≤ 3 points and elevated s-IgG4 to tailor management. In contrast, in patients with c-RI ≤ 3 points and normal s-IgG4, the added yield of18F-FDG PET/CT appears to be low.References[1]Wallace ZS et al. Arthritis Care Res (Hoboken). 2018;70(11):1671-1678[2]Zongfei J et al. Arthritis Research & Therapy. 2022;24(1):106.Table 1.Total cohort (n = 53)Treatment naïve at time of18F-FDG PET/CT, n (%)35 (66)c-RI high disease activity (RI > 3), n (%)23 (43)c-PET-RI high disease activity (RI > 3), n (%)38 (72)Factors associated with reclassification to high disease activity after18F-FDG PET/CTOR95% CIp-valueElevated s-IgG4 (> 2.01 g/L)16.01.7-154.60.017s-IgG4 (per g/L unit increase)1.51.1-2.20.020CRP (per mg/L unit increase)1.10.9-1.30.317Acknowledgements:NIL.Disclosure of InterestsJens Vikse Speakers bureau: Boehringer-Ingelheim, Novartis, Consultant of: Jupiter Life Science, Novartis, Øyvind Midtvedt: None declared, Øyvind Molberg: None declared, Bjørg Tilde Svanes Fevang Speakers bureau: UCB, Consultant of: Lilly, Øyvind Palm: None declared, Torhild Garen: None declared, Katrine Brække Norheim: None declared, Mona Revheim: None declared, Kjersti Johnsrud: None declared, Håvard Fretheim Speakers bureau: Boehringer Ingelheim, Consultant of: Bayer, Grant/research support from: GSK/Actelion, Marianne Wallenius: None declared, Gunnstein Bakland Consultant of: UCB, Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Consultant of: ARXX, Boehringer Ingelheim, Genentech, Jannsen, Medscape, Merck Sharp & Dohme and Roche, Grant/research support from: Boehringer Ingelheim, Jannsen.
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Bansal, Radhika, Sagar Rakshit, Katrina Glazebrook, Prashant Kapoor, Francis K. Buadi, Martha Q. Lacy, Morie A. Gertz, et al. "Comparison of Conventional Xrays with CT Based Approaches for Detection of Lytic Lesions in Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-138686.
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Background: Lytic bone lesions are one of the most common clinical characteristics of patients with multiple myeloma (MM) and identification of bone lesions help distinguish between patients with smoldering multiple MM and active MM. Given this, the most recent update of the diagnostic criteria for MM incorporates advanced imaging approaches for distinguishing between the two entities. Several small retrospective studies have compared conventional skeletal survey (SS) with whole-body low dose computed tomography (WBLDCT) scan or the CT portion of a positron emission tomography (PET) scan. Conducting prospective studies comparing these two modalities side by side is limited by the radiation exposure. We undertook this study to provide a comparison between these two imaging modalities in terms of their ability to recognize lytic bone lesions in patients with MM. Patients and methods: This was a retrospective study of consecutive patients with the diagnosis of MM treated at Mayo Cinic Hospital during 2004- 2018. Patients were included if they had a conventional skeletal survey no more than 3 months before MM diagnosis or any time after diagnosis and also had a WBLDCT or PET-CT within a 12-month period following the skeletal survey. We chose this approach since it is unlikely that a patient would have had both modalities done at the same time as part of standard of care (SOC). This approach was also facilitated by a gradual change in our SOC for skeletal imaging from conventional skeletal survey to WBLDCT. To measure the robustness of our findings, we performed a sensitivity analysis in patients who had the exam ≤6 months apart. Proportions were compared using a chi-square test and survival estimates were calculated using the Kaplan- Meier methodology and compared using log rank test. Results: The overall study cohort had 1040 patients, median age was 62 years at diagnosis (range, 24-94), 61% were male and 39% were female. The median time to the skeletal survey was 8 months from diagnosis (range, 0-160) and the median time to WBLDCT or PET-CT from SS was 2 months (0-12). A PET-CT was available in 789 (76%) of patients and WBLDCT in 251 (24%) of patients. Among the 300 patients with no lesions identified by SS, 188 (63%) had lytic lesions identified by CT, while in 60/740 (8%) patients with a positive SS did not have lytic lesions observed on the CT (p<0.0001). Overall, CT identified lytic lesions in 868 (84%) patients compared with 740 (71%) patients with lytic lesions seen on SS. Although the proportion of lytic lesions was slightly higher with PET compared to WBLDCT, the analysis did not reach statistical significance (65% vs. 56%; p = 0.17; Table 1a). After restricting the analysis to those with ≤6 months gap between low dose CT and SS (n=737), the result did not change (Table 1b). Further examination demonstrated that presence of lytic lesions by SS had no impact on OS from diagnosis, detection of lesions on the CT exam was associated with an inferior survival (112 vs. 81 months, p<0.0001). (Figure 1) Conclusion: Skeletal survey has been the screening technique of choice for evaluation of bone involvement in MM for decades. However, CT based approaches have higher sensitivity with lytic lesions identified in a higher proportion of patients. The prognostic value of lytic disease is evident with CT based detection, again suggesting that this provides a more accurate estimate of the skeletal disease burden. Low dose CT rather than conventional radiographs should be the modality of choice for monitoring disease-progression and diagnosing active multiple myeloma. Disclosures Kapoor: Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Gertz:Abbvie: Other; Celgene: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau; Annexon: Other: personal fee; Research to Practice: Other; Sanofi: Other; Proclara: Other; DAVA oncology: Speakers Bureau; Springer Publishing: Patents & Royalties; Appellis: Other: personal fee; Amgen: Other: personal fee; Prothena: Other: personal fee; Aurora Bio: Other; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee. Dispenzieri:Takeda: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding. Dingli:Alexion: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Apellis: Consultancy; Karyopharm Therapeutics: Research Funding. Lin:Merck: Research Funding; Takeda: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy. Kumar:Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding.
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De Jongh, J., R. Hemke, G. C. J. Zwezerijnen, M. Yaqub, I. Van der Horst-Bruinsma, M. G. H. Van de Sande, A. Van Kuijk, et al. "POS1071 [18F]FLUORIDE PET-CT SCANS VISUALIZE BOTH AXIAL AND PERIPHERAL BONE FORMATION IN PSORIATIC ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 859–60. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1259.
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BackgroundPsoriatic arthritis (PsA) can present with peripheral (i.e. arthritis, enthesitis, dactylitis) and/or axial (spondyloarthritis) manifestations. Positron Emission Tomography (PET) may be a promising imaging technique for detection of whole body disease activity since it combines quantification and picomolar sensitivity for accurate depiction of pathologic processes with anatomical low dose CT imaging as a reference (3, 4). It was recently demonstrated that [18F]Fluoride PET-CT scans can successfully visualize and monitor ankylosing spondylitis disease activity by imaging of bone formation in the axial skeleton (5). Since bone formation is associated with enthesitis and synovitis in PsA, [18F]Fluoride may enable sensitive, whole body detection of disease activity in PsA.ObjectivesTo investigate the feasibility of [18F]Fluoride PET-CT to visualize disease activity of PsA by imaging of bone formation at axial and peripheral sites in PsA patients.MethodsSixteen patients (female 10/16, age 50.6 ±8.9 years) with PsA fulfilling CASPAR criteria and clinically active disease including ≥1 clinically active enthesitis site were included. Clinical disease activity was assessed by swollen joint count/tender joint count 44, MASES and SPARCC. Of each patient, a whole body [18F]Fluoride PET-CT scan at 45 minutes post injection was performed. All scans were dichotomously scored by two board certified readers (blinded for clinical data) for PET-positive lesions in the joints, peripheral enthesis sites and spine. Low dose CT was used for anatomical reference.ResultsOut of 1088 evaluated joints, 109 joints showed PET enhancement, most frequently in the interphalangeal- and metatarsal joints of the feet (14/109, 12,9%) (Figure 1A) and the distal interphalangeal joints of the hands (14/109, 12,9%). Out of 416 evaluated entheseal sites, PET positivity was found at 44 sites, mainly located at the patella tendon insertion (11/44, 25%) (Figure 1B) and the quadriceps tendon insertion (10/44, 22.7%). Of the PET positive joints and entheses sites, respectively 81.1% and 70.5% were not associated with tender or swollen joints and clinical enthesitis, respectively. In 11 out of the 16 patients ≥1 axial PET positive lesion was observed (Figure 1C), most frequently located in the cervical spine (19/49 observed axial lesions, 38.8%). Two patients showed PET enhancement in one sacro-iliac joint (SIJ) without any inflammatory back pain (IBP). Only four out of 15 patients reported IBP and missing data for 1 patient. In two patients clinical dactylitis was observed which was also depicted on PET-CT.Figure 1.[18F]Fluoride uptake in the metatarsal and IP-joints of the feet (A), in the patella tendon (B) and in the spine (C)Conclusion[18F]Fluoride PET-CT scans can visualize disease activity at whole body musculoskeletal manifestations of PsA by demonstrating local bone formation in joints, entheses and the axial skeleton. By sensitive imaging of bone formation at active sites, [18F]Fluoride PET-CT adds information to clinical disease activity, reflected by a high number of clinically negative, PET positive sites on top of concordant findings.References[1]Kaeley GS, Eder L, Aydin SZ, Gutierrez M, Bakewell C. Enthesitis: A hallmark of psoriatic arthritis. Semin Arthritis Rheum. 2018;48(1):35-43.[2]Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriatic arthritis. Rheumatology (Oxford). 2020;59(Suppl 1):i37-i46.[3]von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT: current applications and future directions. Radiology. 2006;238(2):405-22.[4]Jones T. The role of positron emission tomography within the spectrum of medical imaging. Eur J Nucl Med. 1996;23(2):207-11.[5]Bruijnen STG, Verweij NJF, van Duivenvoorde LM, Bravenboer N, Baeten DLP, van Denderen CJ, et al. Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography. Rheumatology (Oxford). 2018;57(4):770.AcknowledgementsWe thank Pfizer and Novartis for financial support of this investigator initiated study.Disclosure of InterestsJerney de Jongh: None declared, Robert Hemke: None declared, Gerben C.J. Zwezerijnen: None declared, Maqsood Yaqub: None declared, Irene van der Horst-Bruinsma Speakers bureau: BMS, AbbVie, Pfizer, MSD, Consultant of: AbbVie, UCB, MSD, Novartis, Eli Lilly, Grant/research support from: Unrestricted Grants received for investigator initiated studies from MSD, Pfizer, AbbVie, UCB, Marleen G.H. van de Sande Speakers bureau: UCB, Consultant of: Advisory board AbbVie, Eli Lilly, Novartis, UCB, Grant/research support from: Novartis, Janssen, UCB, Eli Lilly, Arno Van Kuijk Speakers bureau: Novartis, Consultant of: Novartis, AbbVie, Janssen, Irene Bultink Speakers bureau: Eli Lilly, MSD, Amgen, UCB, GSK, Roche, Sanofi Genzyme (outsite the submitted work), Consultant of: Sanofi Genzyme, Astrazeneca (outside the submitted work), Lot Burgemeister Consultant of: Advisory board Novartis, Galapagos, Nancy M.A. van Dillen: None declared, Alexandre Voskuyl: None declared, Conny J. van der Laken: None declared
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Giollo, A., G. Vinco, G. Orsolini, G. Cioffi, G. Adami, A. Fassio, L. Idolazzi, et al. "AB1094 SCAR IMAGING ECHOCARDIOGRAPHY WITH ULTRASOUND MULTI-PULSE SCHEME [eSCAR] FOR THE DETECTION OF MYOCARDIAL FIBROSIS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: PRELIMINARY RESULTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1836.2–1836. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5006.
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Background:Myocardial fibrosis is a severe complication of immune-mediated diseases, occurring in up to 30% of systemic lupus erythematosus (SLE) patients. Cardiovascular magnetic resonance imaging allows myocardial scar detection in SLE patients, but it is costly, time consuming, and unfit for patients with renal disease. Scar imaging echocardiography with ultrasound multi-pulse scheme (eSCAR) is a novel and promising technique that proved to be effective in detecting ischemic myocardial scars in patients with coronary artery disease (CAD).Objectives:To evaluate if the eSCAR technique is feasible and to better characterize SLE patients with cardiac involvement by eSCAR.Methods:We recruited consecutive patients with SLE classified according to the 2019 EULAR/ACR recommendations. Patients with diabetes mellitus, obesity, prior cardiovascular (CV) disease or anti-phospholipid (aPL) syndrome were excluded. Eligible participants underwent a thorough clinical assessment and a full echocardiography examination, including the eSCAR technique. Data on clinical variables were collected; disease activity was estimated by the SLE Disease Activity Index (SLEDAI) score. Lupus flare was defined as new/worse clinical signs and symptoms and/or lab measurements and a change/increase in treatment. Patients were compared according to the presence or absence of eSCAR. In this preliminary report, only descriptive analyses are provided. Continuous data are reported as median [25th; 75thpercentile].Results:We enrolled fifteen patients diagnosed with SLE (age 45 years [36; 47], disease duration 14 years [12; 20]), 13 (87%) were females. Median SLEDAI was 5 [2; 8]. The most frequent disease involvement included arthritis (73%), skin and mucous membranes (60%), lupus nephritis (47%) and cytopenias (47%). Patients had received treatment for lupus with 5 drugs [5; 8]. Cumulative prednisone dosage was 25 g [20; 44], whilst the current daily dosage of prednisone was 4 mg [0.0; 5.0]. Hypertension was present in 4 (27%) and hypercholesterolemia in 2 (13%) subjects; 4 patients (27%) were current or past smokers. The eSCAR technique was feasible in all participants with no adverse effects. Myocardial scars were detected in 2 patients (eSCAR-positive 13%; figure and table); eSCAR positive patients were females and had no history of cardiovascular involvement (including pericarditis); they had at least one relapse within the prior 12 months before enrollment; at least one cardiovascular risk factor was found in both patients (one was a smoker and the other one had hypertension); none received prior treatment with cyclophosphamide or rituximab; they had no renal involvement; arthritis and cytopenia were the prominent features of disease; anti-dsDNA titer was higher than eSCAR-negative patients.Conclusion:Echocardiography allowed detection of myocardial scars in patients with SLE. Our preliminary data show that eSCAR is feasible and well tolerated in a SLE population. Further data from this ongoing study will help investigate whether eSCAR might improve risk stratification, by identifying myocardial involvement in SLE patients with a more active disease.eSCAR positivePatient 1eSCAR positivePatient 2eSCAR negativeSLE patients (n=13)Age, years324545SexFemaleFemale11 F / 2 MESR mm/h29715CRP mg/L30.62Anti-dsDNA (IF)PositivePositivePositive 7 (47)Anti-dsDNA (CLIA)10514934 [7; 66]C3 (mg/L)618085 [70; 94]C4 (mg/L)41310 [9; 16]P-Cr (mg/dL)0.60.80.7 [0.6; 0.7]aPLPositiveNegative7 (47)Disease duration, years152814 [12; 15]SLEDAI1205 [2; 8]Lupus flare in the past 12 monthsyesyes5 (33)Cumulative prednisone dosage (g)606124 [19, 32]Previous use of cyclophosphamideNoNo3 (20)Previous use of rituximabNoNo1 (1)Acknowledgments:This study was granted by Gruppo LES Italia OnlusDisclosure of Interests:Alessandro Giollo: None declared, Giulia Vinco: None declared, Giovanni Orsolini: None declared, Giovanni Cioffi: None declared, Giovanni Adami: None declared, Angelo Fassio Speakers bureau: Angelo Fassio reports personal fees from: Abiogen and Novartis, outside the submitted work., Luca Idolazzi: None declared, Davide Gatti Speakers bureau: Davide Gatti reports personal fees from Abiogen, Amgen, Janssen-Cilag, Mundipharma, outside the submitted work., Flavio Luciano Ribichini: None declared, Maurizio Rossini Speakers bureau: AbbVie, Abiogen, Amgen, BMS, Eli-Lilly, Novartis, Pfizer, Sanofi, Sandoz and UCB, Ombretta Viapiana: None declared
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Harwood, Vanessa, Alisa Baron, Daniel Kleinman, Luca Campanelli, Julia Irwin, and Nicole Landi. "Event-Related Potentials in Assessing Visual Speech Cues in the Broader Autism Phenotype: Evidence from a Phonemic Restoration Paradigm." Brain Sciences 13, no. 7 (June 30, 2023): 1011. http://dx.doi.org/10.3390/brainsci13071011.
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Audiovisual speech perception includes the simultaneous processing of auditory and visual speech. Deficits in audiovisual speech perception are reported in autistic individuals; however, less is known regarding audiovisual speech perception within the broader autism phenotype (BAP), which includes individuals with elevated, yet subclinical, levels of autistic traits. We investigate the neural indices of audiovisual speech perception in adults exhibiting a range of autism-like traits using event-related potentials (ERPs) in a phonemic restoration paradigm. In this paradigm, we consider conditions where speech articulators (mouth and jaw) are present (AV condition) and obscured by a pixelated mask (PX condition). These two face conditions were included in both passive (simply viewing a speaking face) and active (participants were required to press a button for a specific consonant–vowel stimulus) experiments. The results revealed an N100 ERP component which was present for all listening contexts and conditions; however, it was attenuated in the active AV condition where participants were able to view the speaker’s face, including the mouth and jaw. The P300 ERP component was present within the active experiment only, and significantly greater within the AV condition compared to the PX condition. This suggests increased neural effort for detecting deviant stimuli when visible articulation was present and visual influence on perception. Finally, the P300 response was negatively correlated with autism-like traits, suggesting that higher autistic traits were associated with generally smaller P300 responses in the active AV and PX conditions. The conclusions support the finding that atypical audiovisual processing may be characteristic of the BAP in adults.
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Sims, Matthew, Sahil Khanna, Darrell Pardi, Paul Feuerstadt, Charles Berenson, Henry Wu, Elaine E. Wang, Elaine E. Wang, Barbara McGovern, and Lisa von Moltke. "658. Diagnostic Testing Among Patients with Suspected Recurrent Clostridioides difficile Infection (rCDI) in ECOSPOR III a Phase 3 Clinical Trial: Implications for Clinical Practice vs Clinical Trials." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S431. http://dx.doi.org/10.1093/ofid/ofab466.855.
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Abstract Background Accurate diagnosis of rCDI is challenging because of limitations in test performance and alternative causes of recurrent diarrhea, such as post-infectious irritable bowel syndrome (IBS). Stool enzyme immunoassay (EIA) toxin testing (TOX) is the best predictor of active disease, but may miss cases of CDI when toxins are below the limit of detection. In contrast, glutamate dehydrogenase (GDH) or PCR have high sensitivity but cannot differentiate colonization from infection, leading to possible overdiagnosis due to low specificity. In ECOSPOR III, SER-109, an investigational purified microbiome therapeutic, was superior to placebo in reducing rCDI (12.4% vs 39.8%, respectively; p-value < 0.001). We examined diagnostic testing patterns among screened subjects. Methods Patients with ≥2 prior episodes and ≥3 unformed bowel movements over 48 hours were screened. To ensure enrollment of patients with active CDI, toxin testing was required at entry via a local certified or central lab (Eurofins; Framingham, MA). Subjects with discordant GDH+/TOX- tests at the central lab had reflex confirmatory testing with a cell cytotoxicity neutralization assay (CCNA), considered the “gold standard” for toxin testing. Results The leading reason for screen failure among 281 subjects screened was a negative toxin test (50/99; 50.5%). Of 182 patients enrolled, 59 (32.4%) qualified with EIA TOX+ at the local lab (33 TOX+; 25 GDH+/TOX+) and 122 (67.0%) qualified by the central lab (Table 1). Of these 122 subjects, 87 qualified by GDH+/TOX+ but 35 required additional reflex testing by CCNA due to discordant GDH+/TOX-results; all 35 were positive. Diagnostic Testing for Qualifying C. difficile Episode in ITT Population Conclusion These diagnostic testing patterns suggest a subset of patients with suspected rCDI have toxin concentrations below the EIA threshold for detection or may have an alternative cause of diarrhea, such as post-infectious IBS. Thus, the limitations of EIA toxin testing need to be considered in clinical practice when evaluating patients with compatible symptoms of rCDI and a high prior probability of infection. In contrast, in trials of investigational agents, toxin testing assures enrollment of patients with active disease and accurate estimates of efficacy. Disclosures Matthew Sims, MD, PhD, FACP, FIDSA, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Sahil Khanna, MBBS, MS, Seres (Grant/Research Support) Darrell Pardi, MD, seres (Consultant)Vedanta (Consultant) Paul Feuerstadt, MD, FACG, Ferring/Rebiotix Pharmaceuticals (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Finch Pharmaceuticals (Scientific Research Study Investigator)Merck and Co (Speaker's Bureau)SERES Therapeutics (Consultant, Scientific Research Study Investigator)Takeda Pharmaceuticals (Consultant) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)
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Paul, Shuvo Kumar, Mircea Nicolescu, and Monica Nicolescu. "Enhancing Human–Robot Collaboration through a Multi-Module Interaction Framework with Sensor Fusion: Object Recognition, Verbal Communication, User of Interest Detection, Gesture and Gaze Recognition." Sensors 23, no. 13 (June 21, 2023): 5798. http://dx.doi.org/10.3390/s23135798.
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With the increasing presence of robots in our daily lives, it is crucial to design interaction interfaces that are natural, easy to use and meaningful for robotic tasks. This is important not only to enhance the user experience but also to increase the task reliability by providing supplementary information. Motivated by this, we propose a multi-modal framework consisting of multiple independent modules. These modules take advantage of multiple sensors (e.g., image, sound, depth) and can be used separately or in combination for effective human–robot collaborative interaction. We identified and implemented four key components of an effective human robot collaborative setting, which included determining object location and pose, extracting intricate information from verbal instructions, resolving user(s) of interest (UOI), and gesture recognition and gaze estimation to facilitate the natural and intuitive interactions. The system uses a feature–detector–descriptor approach for object recognition and a homography-based technique for planar pose estimation and a deep multi-task learning model to extract intricate task parameters from verbal communication. The user of interest (UOI) is detected by estimating the facing state and active speakers. The framework also includes gesture detection and gaze estimation modules, which are combined with a verbal instruction component to form structured commands for robotic entities. Experiments were conducted to assess the performance of these interaction interfaces, and the results demonstrated the effectiveness of the approach.
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Gerver, David, Patricia E. Longley, John Long, and Sylvie Lambert. "Selection Tests for Trainee Conference Interpreters." Meta 34, no. 4 (September 30, 2002): 724–35. http://dx.doi.org/10.7202/002884ar.
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Abstract This preliminary study devised and tested a series of psychometric tests to facilitate selection of simultaneous and consecutive interpreter-trainee candidates. Twelve tests, based either on text materials, linguistic subskills or speed-stress, were correlated with judges' ratings of the final interpretation examination. Students who passed the exam had higher mean scores on all tests than those who failed. Test scores were positively inter-correlated between completion-detection tests and simultaneous interpretation ratings and between recall tests and consecutive examination ratings. Text-based tests were more predictive than subskills or speed-stress tests. The relationship between test type and interpreting is discussed together with possible reasons underlying differential performance on tests of the same kind. Problems in the recruitment and training of conference interpreters have been the frequent subject of debate by members of the profession (Keiser 1978; Longley 1978; Namy 1978). Although there have been some publications on psychological and other theoretical aspects of the interpreter's skills (Barik 1973; Gerver 1976; Seleskovitch 1976; Karmiloff-Smith 1978; Moser 1978; Chernov 1979; Lambert 1983), there has been no systematic research on student selection and training in this field. What qualities and skills are required for success as an interpreter or as a trainee in the field? Although no previous empirical research has been carried out on this subject, there does appear to be some consensus among interpreters and teachers of interpreting as to the skills and qualities sought in new members of the profession. A survey of articles written by members of the profession, as well as transcripts of interviews with working interpreters, suggested some agreement of the following as being essential for success as a trainee or in the profession. 1. Profound knowledge of active and passive languages and cultures. 2. Ability to grasp rapidly and convey the essential meaning of what is being said. 3. Ability to project information with confidence, coupled with a good voice. 4. Wide general knowledge and interests, and a willingness to acquire new information. 5. Ability to work as a member of a team. The specific aim of the present study was to develop and evaluate objective tests to assess the second item mentioned above, that is the candidate's ability to grasp rapidly and to convey the meaning of spoken discourse. It was expected that the tests would contribute to improving selection procedures, hence the number of students passing the final examination, as well as the course itself. The present study arose from the decision of Patricia Longley, one of the co-authors and former director of the Interpretation Programme at the Polytechnic of Central London, to initiate the establishment of objective criteria for the selection of students for the postgraduate course in conference interpreting techniques at the School of Languages in London. The course, founded by Patricia Longley in 1963, and now headed by Jennifer MacKintosh, is an intensive six-month course in simultaneous and consecutive interpretation. Over 200 applications are received each year from candidates throughout the world, about half of whom are invited to London for interviews and informal tests, lasting a day. Only 25 to 30 candidates are selected for the course. The informal tests consist of written translation tests in addition to tests of both aural and oral language skills in the candidates' other languages. During the tests, candidates are first asked to repeat texts in the source language (shadowing) before progressing to interpretation of texts from their passive languages into their active language. These texts progress from simple sentences to more complex, albeit non-technical, longer passages. Unusual and unexpected phrases are inserted into the more difficult passages for interpretation in order to assess candidates' skills in coping with the unexpected and with passages which cannot be translated word-for-word. The interviews are designed to assess candidates' general background knowledge and interests, motivation, presentation of self, and general suitability for the profession. Whether or not there is a current market for the candidate's particular language combination is also taken into account at the time of selection. The intensive, six-month course involves training in both simultaneous and consecutive interpretation, and in the note-taking skills essential to the latter form of interpreting, in conference practices, and in a variety of subjects likely to be encountered in conference settings. The final examinations are oral in both forms of interpretation in the candidate's principal working languages, and are conducted by a board of external examiners who are themselves senior practising interpreters in major international organizations such as the U.N., Council of Europe, I.L.O., and the W.H.O. A secondary aim of the study was to explore alternative types of tests. Since the task of the interpreter is to transform spoken textual information from one language into another, either immediately (for simultaneous interpretation) or after some delay (for consecutive interpretation), the first type of test - termed text-based - assumed the processing of connected discourse to be a crucial feature of the interpreter's task. The approach was based on recent work in the area of text processing (Kintsch 1974; MacKintosh 1985). Text-based tests required either the recall of the information presented or the completion of individual target words in the text. The second type of test - termed subskill-based - assumed language subskills such as synonym generation, sentence re-expression and vocabulary selection to be an adequate reflection of the interpreter's task. The approach was based on the development of a set of factor referenced cognitive tests of verbal ability (Eckstrom et al. 1976). In addition, both simultaneous and consecutive interpretation are performed under conditions of speed-stress, since the interpreter is paced by the speaker over whom he has little or no control. Hence, the third type of test - termed stress-based-assumed speed stress to be a general performance factor not particular to, but exemplified by, interpreting. The approach was based on the development of a speed test requiring the solution of problems involving letter series performed under a time constraint (Furneaux 1956). It was expected that the present research would throw some light on whether text-based, subskill-based or speed stress-based tests reflected the crucial features of the interpreter's task for the purpose of testing trainee candidates' abilities.
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Bruni, C., L. Tofani, H. Fretheim, S. Liem, A. Velauthapillai, H. J. Bjørkekjær, I. Barua, et al. "POS0388 DEVELOPING A SCREENING TOOL FOR THE DETECTION OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS: THE ILD-RISC RISK SCORE." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 449–50. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2722.
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BackgroundHigh resolution computed tomography (HRCT) is the gold standard for the diagnosis of systemic sclerosis associated interstitial lung disease (SSc-ILD). Although there is agreement in performing HRCT as a screening test at time of SSc diagnosis, some physicians do not regularly perform baseline HRCTs. In addition, it is unclear according to which criteria HRCTs should be repeated during the follow-up of baseline ILD negative patients.ObjectivesTo develop a risk score for the presence of SSc-ILD (the ILD-RISC), to guide physicians in ordering both baseline and follow-up HRCTs.MethodsThe steering board included six SSc-ILD experts from referral centers, two fellows and a patient research partner. Items for regression analysis were selected according to face validity, feasibility, scientific background, and personal experience using the nominal group technique (NGT). The prediction model for the presence of ILD was developed from baseline visits of SSc patients from the six centers using multivariable logistic regression with backward selection. Patients were randomly divided into a derivation and validation cohort consisting of 66% and 34% of patients respectively. Patients with missing data in the selected covariates and in the ILD status (outcome) were excluded. After identifying a cut-off favoring sensitivity >85% from the ROC curve analysis, the derived ILD-RISC score was applied first in the validation cohort and then longitudinally in a cohort of SSc patients with negative baseline HRCT.ResultsThe steering board selected 13 variables deemed important in the identification of SSc-ILD: sex, age, disease duration from first non-Raynaud’s phenomenon symptom, skin subset (diffuse/limited), presence of esophageal symptoms, digital ulcers (DU) ever, arthritis ever, smoking ever, increased inflammatory markers, NYHA functional class, SSc autoantibody status (SSc_Atb), FVC% and DLCO%. Among 780/3240 patients fulfilling the inclusion criteria, 533 (43% ILD) and 247 (48% ILD) respectively constituted the derivation and the validation cohort. In the derivation cohort, a model including FVC%, DLCO%, DU ever, age and SSc_Atb (Table 1A) showed an OR of 133.9 (95% CI 53.4-335.9) and an AUC of 79.1% (95% CI 75.3-83.0%) for the presence of ILD on HRCT (Figure 1). An ILD-RISC score ≥0.3 showed sensitivity of 85.6% and specificity of 53.6%, NPV of 83.2% and PPV of 58.2%, which were replicated in the validation cohort (Table 1B). Among 819 patients with negative baseline HRCT, 170 (20.8%) developed ILD during a 3.8±3.0 years follow up (1988 visits). Longitudinally, the ILD-RISC score showed comparable sensitivity and specificity (Table 1B).Table 1.A)ILD-RISC MODEL VARIABLESOR95% CIp valueDigital ulcers, ever2.0581.347-3.145<0.001Age1.0261.010-1.0420.001SSc_ATBAnti-centromere0.3340.198-0.563<0.001Anti-topoisomerase I2.3791.326-4.2670.004Anti-RNA-polymerase III1.4070.636-3.1130.399Anti-Pm/Scl2.5560.916-7.1350.073None of the aboveComparatorFVC%0.9900.979-1.0020.091DLCO%0.9710.960-0.982<0.001B)ILD-RISC SCORE PERFORMANCEDerivation cohortValidation cohortLongitudinal cohortAll Patients/ILD patients533/229247/119819/170AUC %, 95% CI79.1 (75.3 – 83.0)76.4 (71.0 – 82.7)72.6 (68.9 – 76.2)Sensitivity %, 95% CI85.6 (80.4 – 89.9)85.7 (78.1 – 91.5)80.4 (73.9 – 86.0)Specificity %, 95% CI53.6 (47.8 – 59.3)49.2 (40.3 – 58.2)50.5 (48.2 – 52.9)Negative Predictive Value %, 95% CI83.2 (77.2 – 88.1)78.8 (68.2 – 87.1)96.3 (94.9 – 97.4)Positive Predictive Value %, 95% CI58.2 (52.7 – 63.5)61.1 (53.2 – 68.5)13.9 (11.8 – 16.1)ConclusionWe developed and validated the ILD-RISC score to predict the presence of ILD at time of diagnosis and evaluated its performance during follow-up. The ILD-RISC may be useful in routine practice when resources for HRCTs might be limited. In particular, it may also help to decide when to order HRCTs at follow up, thus limiting unnecessary HRCTs and reducing the burden for patients and institutions.Disclosure of InterestsCosimo Bruni Speakers bureau: Actelion, Consultant of: Boehringer-Ingelheim, Eli-Lilly, Grant/research support from: New Horizon fellowship, FOREUM, EUSTAR, GILS, Lorenzo Tofani: None declared, Håvard Fretheim: None declared, Sophie Liem: None declared, Arthiha Velauthapillai: None declared, Hilde Jenssen Bjørkekjær: None declared, Imon Barua: None declared, Ilaria Galetti: None declared, Alexandru Garaiman: None declared, Mike O. Becker Speakers bureau: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Consultant of: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Grant/research support from: Mepha, MSD, Novartis, GSK, Bayer and Vifor, Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Janssen, MSD, Lilly, Roche, Boehringer-Ingelheim, Medscape., Jeska de Vries-Bouwstra Speakers bureau: Payment for presentations and educational events by Boehringer Ingelheim and Janssen, Consultant of: Janssen and Boehringer Ingelheim, Abbvie, Grant/research support from: Roche, Galapagos and Janssen, ZonMW and ReumaNederland, Madelon Vonk: None declared, Jörg H.W. Distler Shareholder of: J.H.W.D. is stock owner of 4D Science and Scientific head of FibroCure., Grant/research support from: J.H.W.D. has received research funding from Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB., Marco Matucci-Cerinic Speakers bureau: Biogen, Bayer, Boehringer-Ingelheim, CSL Behring, Eli-Lilly., Consultant of: Actelion, Biogen, Bayer, Boehringer-Ingelheim, CSL Behring, Eli-Lilly., Grant/research support from: Actelion, Oliver Distler Speakers bureau: Bayer, Boehringer Ingelheim, Janssen, Medscape, Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur, Grant/research support from: Kymera, Mitsubishi Tanabe, Boehringer Ingelheim
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Napolitano, Mariasanta, Simona Raso, Maria Francesca Mansueto, Salvatrice Mancuso, Matteo Nicola Dario Di Minno, Dalila Scaturro, Giulia Letizia Mauro, Giovanni Di Minno, and Sergio Siragusa. "Combined Point of Care Tools Are Able to Improve Treatment Adherence and Health-Related Quality of Life in Patients with Severe Hemophilia: An Observational Prospective Study." Blood 134, Supplement_1 (November 13, 2019): 3455. http://dx.doi.org/10.1182/blood-2019-128129.
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Introduction: Ultrasound (US) assessment of joints is an evolving point of care tool for the detection of early joint arthropathy (Napolitano M, Kessler CM. Hemophilia A and B. Consultative Hemostasis and Thrombosis, Kitchens, 4th edition); population pharmacokinetic (pop-PK) studies are adopted as a useful instrument to set the prophylaxis regimen for patients with hemophilia, they may improve adherence (Nagao A.et al. Thromb Res. 2019 Jan; 173:79-84) and reduce the annual bleeding rate (ABR). Adherence to continuous intravenous administrations of factor VIII or Factor IX products is challenging, thus patients may experience breakthrough bleedings while on prophylaxis. Repeated US examinations of joint status have recently been advocated to attempt to remedy sub-optimal medication adherence (Di Minno A et al., Blood Rev. 2019 Jan;33:106-116). Aim of the current prospective analysis was to evaluate the impact of combined US assessment and pop-PK study on adherence to treatment and health related quality of life in patients with severe hemophilia A(HA) and B (HB) under regular prophylaxis. Material and methods: This prospective observational study was performed at a single tertiary center from January 2017 to June 2019. Research was conducted following the Helsinki Declaration. All patients included in the study provided a written informed consent for study participation. Patients with severe HA and HB routinely underwent, as part of regular 12-months follow-up visits, the following: US joints evaluation of elbows, knees and ankles using the HEAD-US protocol, treatment adherence evaluation by VERITAS-Pro questionnaire, health -related quality of life assessment by the standardized EQ-5D,EQ-VAS and pop-PK study (WAPPS-Hemo, McMaster University) as needed (i.e.in case of changes in life style, planned treatment switch); each patient visualised US and his estimated PK profile during medial encounters. Compliance to the prescribed treatment was also determined by analysis of patient diaries with infusion logs. Statistical analysis was performed using the SPSS software version 25.0 (SPSS Chicago, IL). Statistical tests were 2-sided, with a significance threshold of 0.05. Results: Twenty consecutive males with severe haemophilia were included in the current analysis, 13 with severe HA, 2 with HA with previous inhibitors and 5 HB, with a median age of 30 (range 14- 56) years and a median ABR of 5 (range:0-12). Nine patients were under primary prophylaxis, 8 under secondary prophylaxis and 3 under tertiary prophylaxis, they all self-infused at home. Four patients had one target joint and 3 patients had multiple target joints. For each enrolled subject, HEAD-US score, VERITAS-pro, EQ5D and EQ-VAS score were assessed at enrolment (T0) and at 12 (T12) and 24 (T24) months follow-up visits, respectively. Pop-PK was assessed in 11 patients: in 7 (5 HA,2 HB) it was assessed twice, before and after treatment switch to extended half-life (EHL) products, in 4 it was assessed once to modify prophylaxis treatment schedules for a more active life-style (N=2) or weight changes (N=2). Median ABR was 4 at T12 and 3.8 at T24. Reported breakthrough bleeds at T12 were 14, mainly trauma-related (N= 8) or affecting target joints (N=4), they were not reported at T24 in patients with PK-driven modified schedules (N=4) and in 4 patients under EHL treatments. Mean HEAD-US score at T0 resulted 8 (range:0-16), at T24 it was 6 (range:0-16). Mean Veritas-Pro score values were 42.7 at TO, 40.1 at T12 and 38.7 at T24. At T0, EQ-5D mean utility score was 0.82 (range: 0.68-1), at T24, the mean was 0.87 (range:0.72-1). In detail, at 24 months follow-up, there was a statistically significant (p<0.05) improvement in adherence to treatment with particular reference to the dimensions of communication and skipped doses. A tendency toward improved HEAD-US score, higher adherence and better quality of life scores, was observed in particular in patients switched to EHL products at T24, at a mean of 10 months after switching (range: 6-22 months). Conclusion: Several combined measures of haemophilia treatment monitoring, allowing visual assessment of joints status and PK profile estimates by patients have here shown to improve treatment adherence and quality of life in patients with HA and HB, this may be not only related to new available treatments but also to an increased awareness and education of patients. Disclosures Napolitano: BIOFVIIIx: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Shire: Other: Expert Testimony, Speakers Bureau; Kedrion: Other: Expert Testimony, Speakers Bureau; Octapharma: Speakers Bureau; Bayer: Consultancy, Other: Expert Testimony. Di Minno:Novo Nordisk: Speakers Bureau; CSL: Speakers Bureau; Sanofi: Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Kedrion: Speakers Bureau; Pfizer: Speakers Bureau.
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Gigante, L., D. Bruno, V. Feudo, S. L. Bosello, L. Leccisotti, A. Musto, P. G. Cerasuolo, A. Zoli, A. Giordano, and E. Gremese. "THU0306 ROLE OF 18-FDG PET/CT IN DIAGNOSIS AND FOLLOW UP OF LARGE VESSELS VASCULITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 381.1–382. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6176.
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Background:18-FDG PET/CT is a functional imaging method which allows to identify inflammation of vessel walls. The use of PET in large vessels vasculitis(LVV) at disease onset and during follow up is still debate either to confirm clinical remission either to drive the therapy choice. American Society of Nuclear Cardiology (ASNC) recently advanced recommendations aimed to standardize the application of PET in LVV(1).Objectives:The aim of our study was to assess the clinical role of PET performed in patients affected by LVV at the diagnosis and during the follow up.Methods:We retrospectively evaluated PET/CT of 49 patients affected by clinically active LVV according to LVV visual grading (LVG, grading 0-3) and measured the standardized uptake value(SUV) of large vessels. 38 (77,6%) patients were affected by Giant Cells Arteritis and 11(22,4%) by Takayasu Arteritis. 32(65.3%) patients repeated the imaging after a mean follow-up of 11.5±5.4 months.All baseline (T0) and follow up (T1) clinical data of disease activity were collected. Patients were treated according to EULAR LVV management recommendations(2). T0 PET/CT study was performed in patients with a clinically active disease defined by suggestive symptoms/signs and/or high inflammatory markers. The mean disease duration before T1 PET/CT examination was 4 months. T0 PET was performed in 25/49 patients(52%) at the diagnosis of LVV, whereas in 24/49(48%) patients with already diagnosed but active LVV disease.Results:Baseline PET was positive in 21 patients(42.9%). According to ASNC recommendations, 19 patients (38.8%) presented a LVG=3, 2(4.0%) a LVG=2, 6(12.2%) LVG=1 and 22 (44.9%) LVG=0. Patients performing PET at disease onset(75%) had higher LVG score than patients performing PET during the disease course (25%),p=0,002. At T0, aortic, carotid, axillary and subclavian SUV did not correlate with inflammatory markers.Follow up PET/CT studies were performed in 32 patients, 13 (40.6%) with a clinically active disease despite therapy, while 19(59.4%) in clinical remission.Follow up PET was still positive in 8 patients (25%) with a LVG=3, 10 (31.2%) patients presented LVG=1 and 14 (43.8%) LVG=0. T1 PET/CT study showed a significant reduction of SUV values in descending aorta, left and right subclavian arteries, and left and right axillary arteries when compared with first PET/CT study. According to LVG, 12 patients with active PET/CT study at T0 (19 pts) presented a reduction of LVG from score 2 and 3 to grade 1 or 0 (64.2%) at second PET/CT study. Only 3 patients presented an increased LVG score at T1, while in the other 17 patients T1 PET confirmed the previous score. No significant difference was found between LVG scores according with clinical characteristics, but among 8 patients presenting an active T1 PET, 4(50%) were in clinical remission.Conclusion:The use of ASNC recommendations for FDG PET/CT in LVV enables to confirm a metabolically active disease in 40% of patients and in 75% of patients at disease onset, suggesting that post-posing the exam could lead to underrate the real extension of disease. Our data, even if limited, suggest that PET/CT could be crucial in management of patients in clinical remission, detecting patients with still metabolically active LVV. Further prospective studies are necessary to evaluate the role of PET/CT in driving therapeutic strategies.References:[1]Slart R et all - Eur J Nucl Med Mol Imaging, 2018[2]Hellmich et all – Ann Rheum Dis 2018Disclosure of Interests:Laura Gigante: None declared, Dario Bruno: None declared, Vanessa Feudo: None declared, Silvia Laura Bosello Speakers bureau: Abbvie, Pfizer, Boehringer, Lucia Leccisotti: None declared, Alessia Musto: None declared, Pier Giacomo Cerasuolo: None declared, Angelo Zoli: None declared, Alessandro Giordano: None declared, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB
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De Jongh, J., G. C. J. Zwezerijnen, R. Hemke, M. Yaqub, M. G. H. Van de Sande, A. Van Kuijk, A. Voskuyl, and C. J. Van der Laken. "POS0898 EARLY DETECTION OF ANTI-TNF INDUCED CHANGES IN NEW BONE FORMATION IN PSORIATIC ARTHRITIS PATIENTS BY18F-FLUORIDE PET-CT." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 757–58. http://dx.doi.org/10.1136/annrheumdis-2023-eular.869.
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BackgroundNew bone formation in psoriatic arthritis (PsA) can be observed in all musculoskeletal disease domains and can lead to disability due to ankylosis and bridging syndesmophytes [1, 2]. The positive effect of anti-tumor necrosis (anti-TNF) therapy on radiographic damage (e.g. erosion and joint space narrowing) is well known, but there are contradictory findings on its effects on new bone formation [3, 4]. Imaging of new bone formation in PsA is pivotal in order to ascertain the extent and potential therapeutic effects on structural changes at an early stage of treatment. Our group recently demonstrated that molecular new bone formation can be observed in all PsA disease domains, using18F-Fluoride PET-CT scans. Moreover, the ability of this imaging technique to detect early therapeutic effects in ankylosing spondylitis patients was also demonstrated by our group [5].ObjectivesTo investigate whether18F-Fluoride PET-CT scans can detect a change in18F-Fluoride uptake, reflecting a change in new bone formation, after 12 weeks of anti-TNF therapy in clinically active PsA patients.MethodsNine patients (male 4/9, median age 47 (IQR 19)) with PsA fulfilling CASPAR criteria or a clinical diagnosis according to the treating rheumatologist and clinically active disease including ≥1 clinically active enthesitis site were included. In each patient, a whole body18F-Fluoride PET-CT scan was performed prior to and 12 weeks after starting anti-TNF therapy. Scans were independently assessed for PET-positive lesions (dichotomous) by two readers (blinded for clinical data). Fixed sized volumes of interest were drawn on top of visual PET positive lesions as well as on locations where visual PET positive lesions appeared or disappeared before or after treatment. Standardized uptake values corrected for individual integrated whole blood activity concentration (SUVAUC) were used for quantitative analysis. CT was used for anatomical reference.ResultsCombining all PET-positive lesions of all patients, a total of 153 lesions were observed at baseline (89, 30 and 34 in peripheral joints, entheses and spine, respectively). At week 12, a total of 119 PET-positive lesions were observed (69, 13 and 37 in peripheral joints, entheses and the spine, respectively). Grouping all lesions of all patients, there was a decrease in the mean SUVAUCbetween baseline (1.578, SD 0.99) and week 12 of anti-TNF treatment (1.230, SD 0.85) (Figure 1A). Similar results were observed when grouping all lesions of all patients for separate disease domains. Mean SUVAUCchanges between baseline and 12 weeks were -0.294 (SD 0.88), -0.357 (SD 0.69) and -0.300 (SD 0.67) for respectively peripheral joints (Figure 1B), entheses (Figure 1C) and the spine (Figure 1D).Conclusion18F-Fluoride PET-CT detected a change in new bone formation in PsA domains during anti-TNF therapy as early as 12 weeks post-treatment. The data point at a mean decrease of new bone formation in peripheral joints, entheses and axial skeleton.References[1]de Jongh J et al. (18)F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients. Eur J Nucl Med Mol Imaging. 2022.[2]Lories RJ et al. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest. 2005;115(6):1571-9.[3]Goulabchand R et al. Effect of tumour necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis. 2014;73(2):414-9.[4]Sieper J et al. Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis Rheum. 2008;58(3):649-56.[5]Bruijnen STG et al. Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography. Rheumatology (Oxford). 2018;57(4):631-8.Figure 1.SUVAUCat baseline and week 12 when grouping all lesions of all patients (A), peripheral joints (B), entheses (C) and spine (D)Acknowledgements:NIL.Disclosure of InterestsJerney de Jongh: None declared, Gerben C.J. Zwezerijnen: None declared, Robert Hemke: None declared, Maqsood Yaqub: None declared, Marleen G.H. van de Sande Speakers bureau: UCB, Novartis, Janssen, Consultant of: UCB, Novartis, Abbvie, Eli Lily, Grant/research support from: UCB, Novartis, Eli Lily, Arno Van Kuijk Consultant of: UCB, Janssen, Grant/research support from: Janssen, Novartis, Pfizer, Alexandre Voskuyl Consultant of: GSK, Astra Zeneca, Grant/research support from: Boehringer Ingelheim, Conny J. van der Laken Speakers bureau: Janssen, Abbvie, Pfizer, Novartis, UCB Pharma, Galapagos, Paid instructor for: Lilly, Galapagos, Consultant of: UCB Pharma, GSK, Novartis, Grant/research support from: Pfizer, Abbvie, Novartis, GSK, UCB Pharma
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Roux, C., E. Delannoy, M. Cremoni, M. C. Trojani, L. Evenor, D. Graca, J. Genovese, V. Breuil, and B. Seitz-Polski. "AB0110 FEASIBILITY OF AN IL-17A ASSAY IN PATIENTS WITH ACTIVE AXIAL SPONDYLOARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 1234.1–1234. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4401.
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BackgroundIn Spondyloarthritis (SpA), the method of determination of IL-17 is questionable. Indeed, studies measuring plasma levels of IL-17A without stimulation have shown discordant results.ObjectivesThe objective of our study is to show the validity of an IL17 assay method using both innate and acquired immunity stimulation.MethodsWe included volunteer SpAs presenting for consultation between February 2021 and March 2022 in the study. They were axial SpA meeting the ASAS criteria, naïve to any biological treatment, having failed at least two NSAIDs and in need of biological treatment. The control population was issued from a previews cohort of healthy subjects recruited between January 2020 and February 2021. Serum levels of 11 cytokines (IL-17A, IL-6, IL-1β, IFN-γ, IL-12p70, TNF-α, IL-10, IL-5, IL-4, IL-13, and GM-CSF) were measured with and without stimulation by immune ligands (anti-CD3 as a T-cell stimulant, R848 as TLR 7/8 agonist).Clinical evaluation was performed at 3 months after initiation of biological treatment at the discretion of the investigator (anti-TNFα (TNFi) or anti-IL17). The primary outcome was a BASDAI50 response.ResultsA total of 45 patients with SpA (25 males and 20 females; median age, 41 ± 11 years) were included in the study, along with 27 controls (11 males and 16 females; median age 50.5 ± 28 years). Without stimulation levels of the pro-inflammatory cytokines TNF-α, IL-8, IL-6, and IL-1β were significantly increased in the patients with SpA group in comparison to controls and IL-4, IL-5, IL-12p70, and IL-17A levels in all patients with SpA were below the detection threshold (<2,1 pg/mL for IL-17A). After stimulation, Th17 cytokine IL-17A was significantly increased in the patient group with SpA in comparison to controls (IL-17A 317 pg/mL IQR [59–441] versus 59,9 pg/mL IQR [21,2–127], p = 0,0002). On the other hand, the concentration of Th1 cytokines (IFN-γ, IL-12p70 and TNF-α, IL-1β) were lower in the patient group with SpA than in the controls and the cytokines of the Th2 pathway (IL-4, IL-5) were higher in patients with SpA than in controls. Twenty-eight patients were treated with TNFi, and 14 patients with IL-17i. At three months, 55% of the treated patients had a BASDAI decrease of at least 50% (57.1% of the patients treated with TNFi and 64.3% treated with IL17). In SpA, patients, responders had higher baseline IL17A concentration (383 pg/mL IQR [109–887,2] vs. 30 pg/mL IQR [9–133] p = 0.049). A 145 np/mL threshold was defined to distinguish the patients (responders and non-responders). Positive IL-17A activity was determined using receiver operating characteristic analysis, with a sensitivity of 75% and specificity of 88% (Area Under the receiver operating characteristic Curve = 0,88 p = 0,0415).There was no difference in TNF-α levels without or after stimulation between patients who responded to TNFi treatment and those who did not.ConclusionOur study shows the feasibility of a cytokine stimulation method that allows the determination of IL-17A in current practice in axial SpA. The potential interest in guiding the practitioner in their therapeutic choice (IL-17i or TNFi) should be confirmed in future studies.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsChristian Roux Speakers bureau: Novartis, MSD, Lilly, Abbvie, Galapagos, Pfizer, Elodie Delannoy: None declared, mathilde Cremoni: None declared, marie-charlotte trojani: None declared, lea Evenor: None declared, delphine Graca: None declared, Jeremy Genovese: None declared, Véronique Breuil: None declared, Barbara Seitz-Polski: None declared.
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Kobayashi, Masayuki, Nobuhiro Ohno, Tomofusa Fukuyama, Toyotaka Kawamata, Kaoru Uchimaru, and Arinobu Tojo. "BRAF-V600E Mutation on Circulating Cell-Free DNA Is a Promising Biomarker of High-Risk Adult Langerhans Cell Histiocytosis." Blood 124, no. 21 (December 6, 2014): 3209. http://dx.doi.org/10.1182/blood.v124.21.3209.3209.
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Abstract Background: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of Langerhans cells and significant infiltration of immune cells. Although the precise pathophysiology is to be elucidated, oncogenic BRAF-V600E mutation could be detected in LCH lesions from the majority of patients (Badalian-Very, et al. Blood. 2010). Furthermore, Berres ML et al. found that patients with active, high-risk LCH carried BRAF-V600E in circulating CD11c+/CD14+ cell fractions. In patients with various kinds of cancers, circulating cell-free DNA (cfDNA) in peripheral blood contains cancer-derived genomic DNA and has been applied to non-invasive diagnostic procedure, so called liquid biopsy. In the very recent report, BRAF-V600E was successfully detected on cfDNA from patients with colorectal cancer in 100% sensitivity and specificity (Thierry AR, et al. Nature Med. 2014). Then, in this study, we evaluated BRAF mutation on cfDNA as a potential biomarker of LCH using allele-specific quantitative polymerase chain reaction (ASQ-PCR). Methods: We cloned normal and mutant BRAF alleles that include exon 15 and neighboring sequences into pCR2.1 to make the standard curve. cfDNA was prepared from plasma of adult LCH patients and was subjected to genotyping BRAF alleles by ASQ-PCR, which was specifically designed for detection of BRAF-V600E with a 3'-phosphate-modified oligonucleotide blocker according to Thierry AR, et al. Mutant BRAF load was estimated from the standard curve in each assay and was expressed as the percentage of mutant alleles to total number of alleles. Results and Discussion: Plasma cfDNA was prepared from 8 adult patients with LCH listed in Table.1 as well as normal subjects including cancer-free patients. The mean quantity of recovered cfDNA in LCH vs normal was 316.5pg/ml (median, 290.4) vs 92.0pg/ml (median, 91.8). Three high-risk patients with active multiple lesions were positive for BRAF-V600E. In these patients, the mean ratio of mutant BRAF alleles to total was 3.25 % (median, 2.59 %). Next, we compared the sensitivity of ASQ-PCR of BRAF-V600E between cfDNA and cellular DNA in the same blood sample. Naturally, too much more DNA was recovered from mononuclear cells than plasma in the same blood volume, whereas the ratio of mutant to total alleles was more than 10-fold higher in cfDNA, suggesting that LCH-derived genomes are significantly enriched in cfDNA compared with cellular DNA, and that cfDNA is more adequate for liquid biopsy in LCH with BRAF-V600E. Then, in a BRAF-V600E-positive patient, we followed the mutant BRAF load during the course of initial chemotherapy. The ratio of mutant to total alleles was estimated as 1.00% prior to chemotherapy and not detectable after one course of chemotherapy consisting of vinblastine, prednisolone, methotrexate and 6-mercaptopurine. The validity of this ASQ-PCR data was confirmed by a series of routine imaging analysis performed at the same time. Taken together, ASQ-PCR of BRAF-V600E on cfDNA may contribute to planning of risk-based treatment as well as monitoring of treatment efficacy in LCH, especially in an active, high-risk group. A number of BRAF-targeted inhibitors have been approved or under clinical trial for various cancers with BRAF mutant, and one of those, vemurafenib is also active against LCH with BRAF-V600E (Haroche J, et al. Blood. 2013). Hereafter, the utility of BRAF-V600E on cfDNA should be validated in a large cohort of LCH patients. Conclusion: In spite of a very small cohort, we demonstrated the feasibility of BRAF-V600E on cfDNA as a biomarker of active, high-risk LCH. Disclosures: This work was supported by grants from "Japan LCH Study Group" (JLSG). Can't read 3B2 tag because stream don't exist.Tag: _LTable15 Disclosures Kobayashi: Japan LCH Study Group (JLSG): Research Funding. Fukuyama:Pfizer Japan Inc.: Employment. Tojo:Bristol-Myers Squibb.: Research Funding; Chugai Pharmaceutical Co Ltd.: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Celgene: Consultancy; Novartis Pharmaceuticals Japan.: Research Funding, Speakers Bureau.
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Shumnalieva, R., D. Kachakova, R. Kaneva, Z. Kolarov, and S. Monov. "POS0578 CORRELATION BETWEEN EXPRESSION LEVELS OF MIR-155 AND MIR-223 IN SYNOVIAL FLUID AND ULTRASOUND SCORES FOR ACTIVE SYNOVITIS IN RHEUMATOID ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 522.3–523. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3828.
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Background:MicroRNAs (miRNAs) are a class of small, non-coding RNAs that negatively regulate gene expression at posttranscriptional level. In rheumatoid arthritis studies have shown that miRNA are differentially expressed systemically as well as locally in the inflamed joints [1,2]. The correlation between their systemic or local expression levels and scores for disease activity and progression in RA make them possible candidate for biomarkers in the clinical practice.Objectives:To analyze the expression levels of miR-155 and miR-223 in synovial fluid (SF) from RA patients in regard to the ultrasound scores for disease activity.Methods:A total number of 48 RA patients according to the 1987 ACR criteria were included in the study. Expression levels of miR-155 and miR-223 SF were determined by qPCR (SybrGreen technology) and compared to healthy controls (HCs). Relative changes of gene expression levels of the studied miRNAs were calculated by 2-ΔΔCt method. Musculoskeletal ultrasound (MSUS) examination was performed by two independent examiners on ESAOTE, MyLab60 using both grey scale and power Doppler technic. A semi-quantitative assessment of the peripheral joints was performed for detecting joint inflammation and determining the grade of synovial thickening and the degree of vascularization. Ultrasound features for active disease were correlated to the local expression of the studied miRNAs. SPSS was used for statistical analysis.Results:RA SF showed overexpression of miR-155 (in 79.17%, p=1.63x10-4) and of miR-223 (in 79.17%, p=1.64x10-3) when compared to HCs and both miRNAs could be used to differentiate RA patients from HCs (р=8.0х10-5 and р=2.8х10-4, respectively). When we analyzed the correlation between the diagnosis, the expression of miRNAs and the changes on the musculoskeletal ultrasound examination we found a statistically significant correlation between the presence of synovitis and the degree of the power Doppler signal on MSUS and the local expression of miR-223 (p=6.19 x 10-4 and p=0.003, respectively). SF levels of miR-223 correlated also with the degree of synovial hypertrophy on MSUS (p=0.013). The results for miRNA-155 were not statistically significant.Conclusion:The correlation between the local expression of miR-223 and the ultrasound features of active joint inflammation shows that this miRNA might be a better candidate for local disease biomarker than miR-155. Further analysis with larger sets is needed to confirm if altered local miRNA expression could be used in the clinical practice as biomarker for disease activity especially in cases with subclinical synovitis.References:[1]Filková M, Aradi B, Šenolt L, et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. ARD, 2014; 73: 1898-1904.[2]Kriegsmann, M., Randau, T.M., Gravius, S. et al. Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial tissues of patients with rheumatoid arthritis and osteoarthritis. Virchows Arch, 2016; 469, 93–100.Acknowledgements:The study was supported by Grant 14-D/2012 and Grant 60/2013 funded by Medical University-Sofia.Disclosure of Interests:Russka Shumnalieva: None declared, Darina Kachakova: None declared, Radka Kaneva: None declared, Zlatimir Kolarov Speakers bureau: Amgen, Pfizer, Novartis, Abbvie, Roche, Astra-Zeneka, Simeon Monov Speakers bureau: Amgen, Pfizer, Novartis, Abbvie, Roche, Astra-Zeneka
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Hawkes, Eliza A., Geoffrey Chong, Charmaine Smith, Sze-Ting Lee, Leonid Churilov, Joseph McKendrick, William Renwick, et al. "Safety and Efficacy of Induction and Maintenance Avelumab Plus R-CHOP in Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Analysis of the Phase II Avr-CHOP Study." Blood 136, Supplement 1 (November 5, 2020): 43–44. http://dx.doi.org/10.1182/blood-2020-136024.
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Background: Novel strategies are needed to improve upon the 60% cure rate of upfront R-CHOP in advanced DLBCL. Single-agent immune checkpoint inhibition (ICI) has limited efficacy in heavily pre-treated DLBCL (response rate <10%, Ansell JCO 2019), potentially due to residual immunocompromise from prior therapy. Frontline ICI, given when host immunity is relatively intact, may improve these outcomes. Concurrent ICI with R-CHOP is safe (Smith BJH 2020) but corticosteroid-related immunosuppression may negate ICI efficacy. These factors, along with evidence that ICI sensitises non-Hodgkin lymphoma to subsequent chemotherapy (Carreau BJH 2020), support a sequential treatment strategy. Avelumab (Av) is an anti-PDL1 monoclonal antibody with antibody dependent cell cytotoxicity (ADCC) activity which acts synergistically with rituximab (R) in vitro. We report the results of a phase II single arm study assessing safety of 1st line sequential AvR induction, R-CHOP & Av maintenance for DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage II-IV DLBCL and no active autoimmune disease were treated with AvR induction x2 cycles q2-weekly (Av 10mg/kg IV + R 375mg/m2 IV), followed by R-CHOP21 x 6 cycles then Av 10mg/kg x 6 cycles q2-weekly if in complete metabolic response (CMR) post R-CHOP. The primary endpoint was the rate of grade 3/4 immune-related adverse events (irAE). Secondary endpoints included overall response rate (ORR), failure free survival (FFS), overall survival (OS) and overall toxicity. Response was determined centrally by PET-CT (Lugano 2014 criteria). CMR rates by PET-CT post AvR induction and post C2 R-CHOP were exploratory endpoints. Genomic analysis was performed including next generation sequencing (NGS) based sequence variant detection, copy number analysis and structural variant detection. Results: 28 pts were enrolled from Dec 2017 to Oct 2019. Key baseline characteristics included median age 54 yrs (range 20-79); stage III/IV disease 68%; elevated LDH 61%; IPI ≥2 25%. Histology included 21 DLBCL NOS (75%; 14 GCB, 7 non-GCB by Hans algorithm), 6 primary mediastinal B-cell lymphoma (PMBCL; 21%) and 1 EBV positive DLBCL (4%). The study met its pre-specified primary endpoint of G3/4 irAE <30%. Grade 3/4 irAEs included hepatitis (n=1) and rash (n=2). G1/2 irAEs occurred in 71% (20/28) as follows: rash 53%, liver dysfunction 26%, hyper/hypothyroidism 29% and diarrhoea 21%. 79% had G3/4 toxicity, predominantly haematological, related to RCHOP with febrile neutropenia/infection in 28% of pts. ORR post R-CHOP was 89% (all CR) (Figure 1). The ORR to 2 cycles of induction AvR was 60%, including 6 CMR (21%) across all diagnostic/histologic subgroups (n=1 PMBCL, n=2 non-GCB DLBCL, n=3 GCB DLBCL; Figures 1 and 2). Six pts (21%) progressed during AvR induction (with 1 pt completing only 1 x AvR cycle); all subsequently responded to R-CHOP. With a median follow-up of 16 months, 1-year FFS was 76% and OS 89%. Treatment was discontinued early in 5 pts; 2 during R-CHOP due to progressive disease and 3 during Av maintenance (n=1 immune hepatitis; n=1 pulmonary embolism initially reported as pneumonitis; n=1 progressive disease). Alterations in the CD274/PDCDLG2 locus were identified by NGS in 3 of 27 evaluable pts (n=2 PMBCL, n=1 EBV+ DLBCL). Full genomic analysis to identify factors associated with response will be presented. Conclusion: Sequential AvR induction, R-CHOP and Av maintenance in pts with newly diagnosed DLBCL is feasible with a manageable toxicity profile and a high CR rate. Responses to AvR alone were higher than expected based on the relapsed/refractory population and may suggest superior efficacy of ICI in the frontline setting. These results support ongoing sequential studies of immune priming with PD1/PDL1 inhibition prior to R-CHOP in DLBCL. Acknowledgements: Merck KgA for avelumab plus funding. Tour de Cure Scott Canning Early Career Grant (E Hawkes) and Wilson Centre for Lymphoma Genomics for biomarker testing. Disclosures Hawkes: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding, Speakers Bureau; BMS celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Merck Sharpe &Dohme: Membership on an entity's Board of Directors or advisory committees, Research Funding; takeda: Speakers Bureau; Merck KgA: Research Funding. Chong:Merck Serono: Research Funding; Bristol-Myers Squibb: Research Funding; Hutchison Medipharma: Research Funding; Bayer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Servier: Research Funding; Isofol: Research Funding. Blombery:Novartis: Consultancy; Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria. Barraclough:Roche: Other: Conference sponsorship. Keane:Celgene: Honoraria, Other: Travel; BMS: Research Funding; Roche: Honoraria, Other: Travel, Speakers Bureau; MSD Oncology: Honoraria, Other: Travel; Gilead: Honoraria, Other: Travel, Speakers Bureau. Fong:Pfizer: Honoraria; Astellas: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. OffLabel Disclosure: Avelumab is an anti-PDL1 monoclonal antibody. Inhibition of the PD1/PDL1 pathway stimulates anti-tumour immunity.
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Arai, Ayako, Masahide Yamamoto, Maho Sato, Yasushi Onishi, Yoji Sasahara, Hideki Sano, Masayoshi Masuko, et al. "The Outcomes of Systemic Chronic Active EBV Infection Treatment By Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of Japanese Registry Data." Blood 138, Supplement 1 (November 5, 2021): 3965. http://dx.doi.org/10.1182/blood-2021-147046.
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Abstract Background and aims Systemic chronic active Epstein-Barr virus infection (sCAEBV) is classified as T- or NK-cell neoplasms in the WHO classification revised in 2017. Although allogeneic stem cell transplantation (allo-HSCT) is efficacious for sCAEBV, the effects are yet to be analyzed in a large number of cases due to the disease rarity. To investigate the outcomes and the prognostic factors of allo-HSCT in sCAEBV under the definition of the WHO 2017 classification, we analyzed retrospectively using the database of Japanese Society for Transplantation and Cellular Therapy (JSTCT). Methods Data collection We used the clinical data of hematopoietic stem cell transplantation (HSCT) recipients of the Transplant Registry Unified Management Program (TRUMP) sponsored by JSTCT and Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT). Patients who underwent HSCT to cure EBV-associated diseases, secondary hemophagocytic lymphohistiocytosis (HLH), and virus-associated hemophagocytic syndrome between January 1993 and December 2016 were selected in TRUMP database, and on our behalf, JDCHCT sent out survey questions to the institutions of these patients to collect additional data to check if the diagnosis of sCAEBV matches our criteria, to analyze disease status at the time of HSCT, and to evaluate the efficacy of different treatment methods. The diagnosis of sCAEBV sCAEBV was diagnosed according to criteria suggested in 2016 by the Research group of Measures against Intractable Diseases by Ministry of Health, Labour and Welfare of Japan: (1) elevated EBV DNA load in peripheral blood (PB) (> 10 2.5 copies/μg DNA), (2) detection of EBV infection in T or NK cells from the affected tissues or PB, (3) systemic inflammatory symptoms such as fever, lymphadenopathy, liver dysfunction, progressive skin lesions, vasculitis, and uveitis persisting for > 3 months, and (4) exclusion of other possible diseases, such as primary EBV infection, autoimmune disease, immunodeficiencies, and lymphomas. Patients who fulfilled all (1) to (4) were diagnosed as sCAEBV. These criteria are compatible with the definition of sCAEBV described in the WHO definition of 2017. The definitions of disease activities and responses The disease activities are defined in previous reports (Blood. 2012;119, p673 and BMT. 2016;51, p879) as follows: positive of fever, ALT level elevation, vasculitis, progressive skin lesions, or uveitis. We defined the complete resolution of disease activity as complete response (CR) and CR with a significant decrease in PB EBV-DNA load (< 10 2.5 copies/μg DNA) as virological CR (vCR). Results 81 patients who met the diagnostic criteria of sCAEBV were analyzed. The median age at HSCT was 24 years old, and the three-year overall survival rate (3-year OS) was 74.0%. Of 74 patients whose viral load after HSCT evaluated, 49 (66.2%) achieved vCR. The multivariate cox proportional hazard model revealed that advanced age, adolescent and young adult (AYA) (age, 15-39; n = 48) and adult (age, > 40; n = 13), was a risk factor of poor OS. The hazard ratios (HR) of AYA and adult groups were 10.14 and 4.63 respectively. It also showed that the presence of HLH at HSCT (HR 4.55), high sIL-2R (≥ median, 691 U/mL) at HSCT (HR 5.27), and conditioning without total body irradiation (HR 3.23) were independently associated with poor survival. Moreover, the median survival time of patients with active disease and extremely high sIL-2R level (≥ 3 × median, 2073 U/mL) was 0.9 months, whereas the other groups did not reach the median. Conclusion Although HSCT is the only curative treatment for sCAEBV, the strategies need improvements in high-risk cases, especially of high sIL-2R. Disclosures Arai: ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Kyowa Kirin CO., LTD.: Honoraria, Research Funding; Abbvie: Honoraria; BMS: Honoraria; Elsai Co Ltd: Research Funding; Abbott Japan LLC: Honoraria; Nippon Shinyaku Co. Ltd: Honoraria, Research Funding; Otsuka Pharmaceuticals Co. Ltd: Research Funding; Novartis Pharma KK: Honoraria; Takeda Pharmaceuticals Co Ltd: Honoraria, Research Funding; Shionogi & Co Ltd: Research Funding; Asahi Kasri Pharma Corporation: Research Funding; Sanofi: Honoraria; Pfizer japan: Honoraria; Astellas Pharma Inc.: Honoraria. Yamamoto: Bristol-Myers Squibb Company: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; NIPPON SINYAKU CO., LTD: Honoraria; Novartis Pharma: Honoraria; ONO PHARMACEUTICAL CO.: Honoraria; Otsuka Pharmaceutical: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Ichinohe: Repertoire Genesis Inc.: Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria; Celgene: Honoraria; Zenyaku Kogyo Co.: Research Funding; Takara Bio Inc.: Research Funding; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co: Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Eisai Co.: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Co.: Honoraria; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.
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Cilloni, Daniela, Enrico Bracco, Sonia Carturan, Valentina Rosso, Valentina Campia, Alessandra Favole, Chiara Calabrese, et al. "Design and Application of a Novel PNA Probe for the Detection At a Single Cell Level of BCR-ABL T315I Mutation in Chronic Myeloid Leukemia Patients." Blood 120, no. 21 (November 16, 2012): 3732. http://dx.doi.org/10.1182/blood.v120.21.3732.3732.
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Abstract Abstract 3732 Background: The BCR-ABL T315I mutation at the gatekeeper residue is frequent in advanced phases of chronic myeloid leukemia (CML) and is one of the main cause of resistance to Tyrosine Kinase Inhibitors (TKI) by disrupting important contact points between the drugs and the enzyme. Although this mutation can be detected by different techniques and at different levels of the mutated clone, the prognostic significance of the absolute amount of the mutated allele is widely unknown. The aim of the study was to develope a novel assay based on peptide nucleic acid (PNA) technology coupled to immuno-fluorescence microscopy (PNA-FISH) for the specific detection at a single cell level of T315I mutation thus improving both the diagnostic resolution and the knowledge on the behaviour of the mutated clone. Methods: We designed a fluorescently-labelled PNA probe, coupled to FISH technology, which allows to distinguish with a high degree of specificity between CD34+ progenitor stem cells harbouring T315I mutation or the wild type form of BCR-ABL. CD34+ cells were enriched from CML patients who were positive for T315I mutation, or from patients who lost T315I mutation after ponatinib treatment. In addition we tested CML patients without T315I mutation as control and BM samples from healthy donors to establish the specificity of the method. CD34+ progenitors cells were enriched by MACS and then cytospun onto slides and hybridized with human species-specific fluorescinated 15 base pairs (bp)-long oligo-PNA, specifically recognizing the BCR-ABL T315I sequence. Slides were analyzed by fluorescence confocal microscopy. Results: We found, with a rather wide variability occurring among patients, a percentage of mutated CD34+ cells ranging from 3 to 90%. In addition these data indicate that fluorescinated BCR-ABL T315I/PNA probe displays a very high specificity towards a single base-pair mismatch. Interestingly, when evaluating the presence of T315I positive cells collected from a patient who lost the mutation (evaluated by sequencing) after ponatinib therapy and acquired T317 mutation a small amount of T315I positive CD34+ cells were still present. This percent did not exceeded 2% of the total CD34+ cell population. Importantly, the lack of positivity detected in CD34 positive cells from CML patient without mutations or in 20 healthy subjects demonstrates a high specificity of this method. Conclusions: BCR/ABL T315I/PNA probe method displays high specificity and reliability in discriminating cell subpopulations harbouring the mutation. In addition, it allows to analyze the CD34+ population at the single cell level and to monitor the behaviour of the clone at the stem/progenitor cell level. This approach allows to monitor longitudinally the evolution of the mutated population over time, the response to specific drugs active against T315I mutants and to characterization the mutated stem/progenitor cell compartment in patients with CML. Disclosures: Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy.
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Dimier, Natalie, Paul Delmar, Carol Ward, Rodica Morariu-Zamfir, Gunter Fingerle-Rowson, Jasmin Bahlo, Kirsten Fischer, et al. "A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia." Blood 126, no. 23 (December 3, 2015): 720. http://dx.doi.org/10.1182/blood.v126.23.720.720.
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Abstract Introduction The standard primary endpoint in clinical trials of chronic lymphocytic leukemia (CLL) is progression-free survival (PFS). Given the increasingly long follow up required to detect differences in PFS between treatment arms in the era of more efficient therapeutics, valid surrogate endpoints are urgently needed to reduce clinical trial duration, thereby accelerating drug development, reducing costs and allowing patients (pts) earlier access to novel treatment options. Pts with CLL who achieve levels of minimal residual disease (MRD) of <1 clonal cell/10.000 leukocytes in peripheral blood (PB) as determined by multicolor flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) at the end of initial treatment are considered MRD negative, and have been shown to experience significantly improved PFS. This analysis aimed to support the evaluation of MRD response at the end of treatment as a surrogate endpoint for PFS in CLL, based on a retrospective analysis of 3 multicenter, randomized, Phase 3 clinical trials. Methods MRD was prospectively assessed in PB of treatment-naive pts with CLL that participated in the German CLL Study Group CLL8, CLL10 and CLL11 multicenter, randomized, open-label, Phase 3 clinical trials, which included induction treatment followed by observation. The primary endpoint of each study was investigator-assessed PFS. MRD was quantified by 4-color flow cytometry in CLL8 and CLL10, and ASO RQ-PCR in CLL11. Both methods had a detection threshold of 1 CLL cell/10,000 leukocytes. Pts who had no MRD result but had disease progression or died shortly after 6 treatment cycles (within 90 [CLL8 and CLL10] or 56 [CLL11] days of last dose) were included and classed as MRD positive. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on MRD. Log ratio was selected as the most reliable representation of MRD response based on the best model fit. To ensure no systemic bias with pt selection, demographic characteristics and efficacy results for the pt population used in the MRD analysis were compared with the respective intent-to-treat populations for each study. Results PB MRD levels at the end of treatment (CLL8 and CLL10, 75-195 days after last dose; CLL11, 56-190 days after last dose) were assessed in 393, 336, and 474 pts from CLL8, CLL10 and CLL11, respectively. PFS events occurred in 24% to 51% of pts assessed for MRD assigned to the experimental arm and in 34% to 67% assigned to active control treatment. Key efficacy data for the 3 trials are shown in Table 1. To fit a meta-regression model, each study was split into subgroups according to region (CLL8), country (CLL11) or randomly (CLL10). For each subgroup, the PFS hazard ratio (HR) was plotted against the ratio of MRD response rates (MRD negative rate in experimental arm to MRD negative rate in control arm, on a log-scale), and a regression line fitted to reflect the relationship between the two parameters (Figure 1). Circle size represents the weighting of each subgroup to the overall model; least variability in PFS HR have the largest circles. Clustering of circles by study reflects the overall treatment effect (for both MRD and PFS) in the studies. A statistically significant relationship between improved MRD response rates and reduction in the risk of disease progression or death was observed (for each unit increase in log of the ratio of MRD response rates, the log of PFS HR decreases by -0.299; 95% CI, -0.441 to -0.157; p=0.0004). Predictions based on this meta-regression model suggest that risk of progression or death decreases as the ratio of MRD response rates (MRD relative risk: MRD-negative rate in experimental arm/MRD-negative rate in control arm) increases (Table 2); i.e. a larger difference in MRD-response rates leads to lower PFS HR. Conclusion A surrogate endpoint (MRD) should not only provide prognostic value for the specific clinical outcome (PFS), but also evidence that treatment effect on the surrogate endpoint (MRD) reliably predicts treatment effect on the clinical outcome (PFS). Results of the meta-regression model show a significant association between treatment effect on MRD and treatment effect on PFS with regard to chemoimmunotherapy. The findings also suggest that treatment effect on PFS can be predicted based on treatment effect on MRD response. This model supports the use of MRD as a surrogate for PFS in pts with CLL. Disclosures Dimier: Roche: Employment. Delmar:F. Hoffmann-La Roche, Ltd.: Employment, Equity Ownership. Ward:F. Hoffmann-La Roche Ltd: Employment. Morariu-Zamfir:F. Hoffmann-La Roche Ltd: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Fischer:Roche: Other: Travel Grants. Eichhorst:Mundipharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau. Goede:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; GSK: Honoraria; Bristol-Myers Squibb: Honoraria. van Dongen:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. Royalty income for EuroClonality-BIOMED-2 Consortium.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of Patent on detection of IgE+ B-cells in allergic diseases. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of IP on Infinicyt software, Patents on EuroFlow-based flowcytometric Diagnosis and Classification of hematological malignancies, Patents on MRD diagnostics, and Patents on PID diagnostics. Royalty income for EuroFlow Consortium.; BD Biosciences: Other: Educational Lectures and Educational Workshops (+ related travelling costs). Laboratory Services in the field of technical validation of EuroFlow-OneFlow antibody tubes in dried format. Provided by the Laboratory of Medical Immunology, Erasums MC, Patents & Royalties; Roche: Consultancy, Other: Laboratory Services in the field of MRD diagnostics, provided by the Laboratory of Medical Immunology, Dept. of Immunology, Erasmus MC, Rotterdam, NL; Immunostep: Patents & Royalties: Licensing of IP and Patents on immunobead-based dection of fusion proteins in acute leukemias and other tumors. Royalties for Dept. of Immunology, Erasmus MC and for EuroFlow Consortium. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Böttcher:Celgene: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Beckton Dickinson: Honoraria. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. ; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.
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McIlroy, Graham, Neil Smith, Anand Lokare, Karen Beale, and Charalampos Kartsios. "Treatment Failure in Patients Receiving Direct Oral Anticoagulants: Clinical Management and Outcomes from a Single-Center Review of 59 Consecutive Patients." Blood 132, Supplement 1 (November 29, 2018): 5058. http://dx.doi.org/10.1182/blood-2018-99-111108.
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Abstract Several direct oral anticoagulants (DOACs) have been developed that dose-dependently inhibit thrombin or activated factor X and offer potential advantages over vitamin K antagonists (VKAs), such as rapid onset and offset of action, absence of an effect of dietary vitamin K intake on their activity, and fewer drug interactions. DOACs have gained in popularity for the treatment and prevention of recurrence of venous thromboembolism (VTE), and the prevention of stroke/systemic embolism in patients with non-valvular atrial fibrillation (AF). However, the lack of routine monitoring means that their pharmacodynamic effect is rarely determined, leaving patients at potential risk of under- or over-anticoagulation. If adequately anticoagulated, the occurrence of thromboembolism (whether primary or recurrent) constitutes treatment failure; this has been reported in approximately 2% of patients in large DOAC clinical trials. The optimal management of such an event occurring with a DOAC remains unclear. In this study, we sought to characterise DOAC treatment failures in our institution, and to rationalise the subsequent anticoagulation strategies in this setting. All VTE patients starting a DOAC at our centre are followed in a consultant-led clinic. Cases of suspected treatment failure are also referred from other specialities and primary care. Between September 2014 and May 2018, we identified 59 consecutive patients (male/female: 34/25) in whom a DOAC treatment failure was diagnosed, including non-resolution of the presenting complaint, and recurrence of or a new thrombotic event. Patient mean age at DOAC initiation was 56 (23-89) years. The median time from DOAC initiation to failure detection was 42 (3-1055) days. 36/59 (61%) patients were receiving a DOAC for treatment of acute VTE, while 19/59 (32%) patients were treated for the prevention of recurrent VTE and 4/59 (7%) patients were on a DOAC for atrial fibrillation. 4 (7%) patients had a thrombophilia background while 5 patients (8%) had an active cancer diagnosis. On recognition of DOAC failure, 34 patients were on apixaban 5mg bd; 7 were on apixaban 2.5mg bd; 15 failed on rivaroxaban 20mg od; and 1 patient failed on each of rivaroxaban 10mg od, dabigatran 110 mg bd and edoxaban 30 mg od. All patients were compliant with their medication. For apixaban 5mg, the median time to failure was 29 (3-551) days; for apixaban 2.5mg it was 140 (26-441) days; for rivaroxaban it was 82 (20-1055) days. Two thirds of patients (39/59) were switched over to therapeutic low-molecular-weight heparin (LMWH), 6/59 patients (10%) were initiated to warfarin with appropriate LMWH bridging, and 11/59 patients (19%) were switched to an alternative DOAC. 3 patients (5%) continued their existing anticoagulant. Most patients (33/39, 85%) initially switched to LMWH following a median time on parenteral anticoagulation of 57 (14-472) days were subsequently switched to oral anticoagulants: 18% to warfarin, 82% to a DOAC. By the end of follow-up, 37/59 patients (63%) were taking a DOAC, including 8 patients who had been switched back to the anticoagulation regimen that failed at the outset, and a further 4 patients returned to the same drug at a higher dose. Of the remainder, 8 patients (14%) were taking a VKA, 8 patients (14%) remained on LMWH, 1 patient was on aspirin and 5 patients (8%) had stopped their anticoagulation treatment. A diagnosis of post-thrombotic leg was made in 15/36 (42%) patients with acute lower limb VTE who failed their DOAC. There is currently a lack of guidance on how to manage patients who fail initial treatment with a DOAC. To the best of our knowledge our study is the first to record the clinical experience in this challenging patient group. Based on our findings, a common strategy is to switch to therapeutic LMWH. After a successful period of parenteral therapy, most patients were switched back to oral treatment, typically another DOAC. Still this did not seem to prevent post-thrombotic syndrome in 42% of patients who were initially diagnosed with acute lower limb thrombosis. Treatment failure is a recognised risk of nearly all medical therapies including DOACs. It is therefore not surprising to encounter such patients in day-to-day practice. The growth in the number of anticoagulant choices has made it more difficult to know how to respond when one fails. As the use of DOACs continues to expand, this problem - and the need for an evidence-based solution - is likely to grow. Disclosures Smith: BMS: Honoraria, Speakers Bureau. Beale:Daiichi Sankyo: Speakers Bureau. Kartsios:Bayer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Boehringer Inglelheim: Consultancy, Honoraria, Speakers Bureau.
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Claudiani, Simone, Carolina Rosadas, Myra McClure, Maryam Khan, Richard S. Tedder, Andrew J. Innes, Dragana Milojkovic, and Jane Apperley. "Prevalence of Sars-Cov-2 Infection in Patients with Chronic Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 20. http://dx.doi.org/10.1182/blood-2020-142454.
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Background: The new SARS-CoV-2-induced disease (COVID-19) pandemic has represented a huge challenge for the health systems and has been responsible for almost 700.000 deaths worldwide as of 1st August 2020. Older age, male sex, comorbidities, ethnicity and socioeconomic factorsare risk factors for severe COVID-19. While the direct effect of solid cancer on the COVID-19 outcome has been investigated and is still debated, limited information is available on the impact of an underlying hematological malignancy on the risk of contracting SARS-CoV-2, the clinical presentation and the outcome of the infection. We report on the prevalence of SARS-CoV-2 infection in a large cohort of patients (pts) with chronic myeloid leukemia (CML). Methods: We retrospectively investigated the exposure to SARS-CoV-2 through serological testing in a single centre cohort of CML pts. Of more than 600 pts on active follow-up, we have screened 161 pts between 1st June and 27th July 2020. At each consultation, we recorded any exposure to or symptoms of SARS-CoV-2 infection in the preceding 6 months. The Imperial Hybrid DABA, a two-step double antigen binding assay (DABA) for the detection and measurement of total antibody directed to the receptor binding domain (RBD) of SARS-CoV-2 was used for analysis. The cut-off (CO) for positivity is established by adding 0.1 to the average of optical density (OD) obtained for the negative controls. A sample-OD/cut-off (S/CO) value ≥ 1 is considered reactive. Results: 161 CML pts in chronic phase underwent serological testing (median age 54 years (18-92), male n=94). Twenty pts were off TKI (post-alloSCT, n=12; in treatment free remission n=6; pregnancy=1 and intolerance n=1) and 141 were on active treatment (imatinib [n=41], dasatinib [n=38], nilotinib [n=23], bosutinib [n=21], asciminib [n=11], ponatinib [n=6] and K0706 [n=1]). The ethnic distribution was White (n=119), Asian-Indian (n= 24), Asian-Chinese (n=3), Black (n=9), Arab (n=5), Mixed Asian-White (n=1). Eighteen pts (11.2%) have tested positive (Table 1). Thirty-eight pts (23.6%) reported symptoms compatible with COVID-19 of whom 12 (31.6%) were DABA positive. Six of 123 (4.9%) asymptomatic pts also tested positive. The time from onset of symptoms to the date of testing were similar in both seropositive (105 days, range 56-180) and seronegative pts (100 days, range 21-205). The median S/CO ratio was 9.9 (1-23.3) in the symptomatic and 1.5 (1.2-21.4) in the asymptomatic pts. Among the 18 positive pts, the median age at symptom presentation was 54 years (38-75) and 12 were males. The median time from CML diagnosis was 7.6 years (0.2-20) and two pts were post-alloSCT. Ethnicity was White, Asian-Indian, Black in 8 (44.4%), 6 (33%) and 4 (22.2%), respectively. In 15 pts (83.3%) symptoms were absent or mild, moderate in 2 and severe in one patient 2 years post-alloSCT on continuing immunosuppression for GvHD. Only 2/18 had PCR tests for SARS-CoV-2 at the time of infection and both were positive. Of the 16 pts not tested for antigen, 2 had been in close contact with a family member with a PCR-confirmed SARS-CoV-2 infection. In the mild cases, the most frequent symptoms were fever (n=7) and cough (n=6), followed by fatigue (n=2), myalgia (n=2) and anosmia (n=2). One patient presented only with acute limb ischemia, derived from thrombus in the superficial femoral artery. One patient had radiological features of COVID-19 pneumonia, but did not require hospitalization. The only patient with severe COVID-19 developed pneumonia requiring CPAP, was refractory to tocilizumab (anti-IL6), but recovered after starting ruxolitinib (JAK2-inhibitor). The median time to complete resolution of symptoms was 21 days (7-56). Conclusions: The prevalence of infection in our CML pts is similar to that of the overall population, which suggests that they are capable of mounting appropriate antibody response against SARS-CoV-2. Importantly, in seropositive pts symptoms were mild. Of note is the higher prevalence in the BAME community and underlines the potential role of socioeconomic factors in disease transmission. Expansion of this CML cohort and serial antibody testing in seropositive patients will provide further information regarding prevalence and durability of serological responses. Disclosures Milojkovic: Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.
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Lasa, C., J. S. Osorio Chavez, D. Martínez-López, C. Álvarez-Reguera, V. Portilla, J. M. Cifrián-Martínez, I. Ferraz-Amaro, and R. Blanco. "AB1650 LATENT TUBERCULOSIS INFECTION IN PATIENTS WITH RHEUMATIC IMMUNE-MEDIATED DISEASES: PREVALENCE AND SCREENING STRATEGY." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 2060.1–2060. http://dx.doi.org/10.1136/annrheumdis-2023-eular.5674.
Full textAbstract:
BackgroundPatients with rheumatic immune-mediated diseases (R-IMID) with latent tuberculosis infection (LTBI) requiring biologic therapy (BT) are at an increased risk of active tuberculosis (TB). The prevalence of LTBI in patients with R-IMID varies depending on geographical location.An accurate diagnosis and prophylactic treatment of LTBI is crucial to reduce the risk of developing TB. No definitive gold standard exists for diagnosing LTBI. Tuberculin skin test (TST) and interferon-γ release assays (IGRAs) are the most used tests.ObjectivesTo assess:a) Prevalence of LTBI in patients with (R-IMID), b) determine the importance of using a booster test in negative TST, c) to compare TST with the IGRA test in the detection of LTBI in patients with R-IMID and d) to perform a literature review of prevalence of LTBI in different geographical areas and its relationship with R-IMID.MethodsCross-sectional single University hospital study including all patients diagnosed with R-IMID who underwent a TST (±booster) and/or IGRA in a period from 2016 to 2020.If TST was negative, a new TST (Booster) was performed between 1 and 2 weeks after the first TST.Patients were diagnosed with R-IMID by an expert rheumatologist according to well-established ACR/EULAR classification criteria for each R-IMID.LTBI was defined by a positive TST and/or IGRA with no evidence of active TB. Diagnosis with IGRA vs TST was compared using Cohen’s kappa coefficient.We performed a literature review in search of previous prevalence studies of LTBI in patients with R-IMID. This search was performed in the month of August 2022. The aim of this review was to compare the prevalence of LTBI in patients with R-IMID in different geographical areas.ResultsWe included 1117 patients (741 women/376 men), mean age 53±15 years with LTBI. Overall LTBI prevalence was 31.7 % ranging from 25% in SLE up to 33.3% in BD.Results of prevalence compared to other countries are shown inTable 1.Booster was positive in 66 patients (7.7%) out of 857 patients with a negative simple TST. TST (+booster) was positive in 187 patients (22.9%) out of 817 with a negative or indeterminate IGRA test. IGRA test was positive in 30 (3.8%) out of 793 patients with a negative TST(+booster), as it is represented inFigure 1. Cohen’s Kappa coefficient between TST(+booster) and IGRA (QFT-plus), was 0.381.ConclusionLTBI is frequent between patients with R-IMID. LTBI screening is important in patients who need to receive BT. This assessment has to be done performing both TST and IGRA as.complementary methods to ensure the detection of all patients with LTBI, since both tests.can have false negative results, especially in patients with R-IMID receiving.immunosuppressive therapy.Table 1.Prevalence of LTBI in other geographic regions according to underlying R-IMID.Author, year (ref. in text)RegionDiagnostic criteria and study periodPrevalence in R-IMID (%)Prevalence in RA (%)Prevalence in PsA (%)Prevalence in AS (%)Prevalence in SLEPrevalence in BDSoborg, et al (2009)DenmarkTSTand IGRA2005 to March 200719%7%20%9%28%5%Chang, et, al (2011)KoreaTST or IGRA test(2007–July 2009)35%30%22%31%47%29%Mínguez, S, et al. (2012)SpainTST, T-SPOT.TB and QTF-plus2008-201013%20%17%16%22%22%Mariett X,et, al (2012)FranceTST, T-SPOT.TBand QTF-plus(2011)35.2%15.1%9.9%Miras, et al. (2014)SpainTST and T.SPOT.TBAugust 2009 to February 20127%5%Carina Mori Frade Gomes et al. (2015)BrazilTST20.6%12,8%18,8%37.6%D. Perifanou, et al. (2018)GreeceTST and IGRA test2008-201066.7%31 %15%21%Anton C, et al. (2019)BrazilTST13 %4%23%26%M. Sellami et al. (2019)North of TunisiaTST and IGRA test2015-201745.7%21.9%Lamia. Oulkadi, et, al. (2021)MoroccoTST and IGRA test2017 – 20217.7 %15.4 %15.9%2,4%24.8%Shen, et al. (2021)ChinaT.SPOT.TBOctober 2012 and June 2017.29.3%Present seriesSpainTST31.7%29.4%32.5%32.5%25%33.3%Figure 1.Proportion of positives in different test to diagnosis LTBI in R-IMID patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsCarmen Lasa: None declared, Joy Selene Osorio Chavez: None declared, David Martínez-López: None declared, Carmen Álvarez-Reguera: None declared, Virginia Portilla: None declared, Jose Manuel Cifrián-Martínez: None declared, Iván Ferraz-Amaro: None declared, Ricardo Blanco Speakers bureau: Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen, Galapagos and MSD, Consultant of: Abbvie, Pfizer, Roche, lilly, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD, novartis and Roche.