Imaging Biomarkers to Predict Outcomes in Patients with Large B-Cell Lymphoma with a Day 28 Partial Response By PET/CT Imaging Following CAR-T Therapy

Introduction: CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy is now a commonly used treatment for relapsed/refractory (R/R) Large B-cell Lymphoma (LBCL). However, predictors of long-term response remain poorly defined. In particular, partial response (PR) at first tumor assessment at Day 28 (D28) is a source of uncertainty both for clinicians and patients. In the pivotal CAR-T trials for LBCL, approximately half of these patients eventually achieved a complete remission (CR), while the other half experienced progressive disease (PD) (Neelapu et al, NEJM 2017). Herein, we present real-world data on 24 patients achieving a PR on D28 by PET/CT imaging following CAR-T therapy for R/R LBCL. We explore whether differences between baseline and D28 PET/CT imaging might predict progression free survival (PFS), overall survival (OS), best overall response rate (B-ORR), or last overall response rate (L-ORR). Methods: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 24 (32%) as achieving a PR on D28. Two independent radiologists collected baseline (pre-CAR-T therapy) and D28 PET/CT Standard Uptake Value (SUV) max and Total Tumor Metabolic Volume (TMV, in cm 3) using ROVER software. The Intraclass Correlation Coefficients (ICC) as a measure of absolute agreement between two readers was 0.99 for SUV the 0.97 for TMV. There was a strong absolute agreement between the two radiologists. For simplicity of data interpretation and given this concordance we present the results of one reviewer. Univariable Cox regression model was used to calculate PFS and OS. All statistical tests were 2-sided and conducted at the 0.05 level of significance. Results: Of the 24 patients with PR on D28 PET/CT, median follow-up time was 1.9 years with 17 patients (71%) still alive at last follow-up (see Fig 1a). Median age was 51 years-old, 46% were female, 66.7% had stage III/IV disease, all patients had ECOG ≤2, 58% received bridging therapy, and half had ≥3 lines of prior therapy (see Table 1A). Results of the univariable Cox regression model revealed that a lower D28 SUV max (p=0.004), lower TMV at both baseline (p=0.03), and at D28 (p=0.01) may be predictive of better OS. Longer PFS was found with lower D28 SUV max (p=0.002) and lower TMV at both baseline (p=0.01), and D28 (p=0.04). In analysis of B-ORR achieved by PET/CT, half of patients in PR at D28 ultimately achieved a CR (see Table 1B). OS was significantly lower in those with a B-ORR of PR vs CR (p<0.004) (see Fig 1b). The median SUV max at baseline was 14 in those with B-ORR of CR vs 15 in PR (Not Significant (NS)); at D28 median SUV max was 5 in CR vs 7 in PR (p=0.04). The median TMV at baseline was 210 in those with CR vs 861 with PR (p=0.07); at D28 median TMV was 12 in CR vs 26 in PR (NS). There was no significant difference in absolute or percent change between baseline and D28 in either SUV max or TMV; however, the absolute difference in TMV was notably greater in those with B-ORR of PR than CR (793 vs 201) (p=0.08). In analysis of outcome by L-ORR by PET/CT, 11 patients were in CR, while 13 had PD (see Table 1C). The median SUV max at baseline was 14 in those in CR vs 15 in PD (NS); at D28 median SUV max was 5 in those with CR vs 6 in PD (NS). The median baseline TMV was 298 in those with CR vs 591 in PD (NS); the median TMV at D28 was 15 in those with CR vs 21 in PD (NS). There was no significant difference in absolute or percent change between baseline and D28 of either SUV max or TMV based on L-ORR. Conclusion: In this analysis of patients in PR at D28 following CD19-directed CAR-T therapy, D28 but not baseline SUV max was significantly higher in those with a B-ORR of PR; and, in our modeling, lower D28 SUV max may predict favorable PFS and OS. Lower TMV, both at baseline and D28, may also be predictive of longer PFS and OS. Collectively, these findings suggest that for patients achieving a PR at D28, the best predictive factor by imaging for ultimately achieving a CR is lower SUV max at D28 and lower TMV at baseline and D28. These characteristics were also associated with longer PFS and OS. These findings indicate that there may be an intrinsic quality to the tumor itself (e.g. FDG-avidity and metabolic volume) that determines the ultimate outcome from a D28 PR. While further study is warranted, we demonstrate that patients with such characteristics should be identified, monitored closely for relapse, and perhaps be considered for further early intervention. Figure 1 Figure 1. Disclosures Hardy: InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees.

Deep learning models for screening of high myopia using optical coherence tomography

This study aimed to validate and evaluate deep learning (DL) models for screening of high myopia using spectral-domain optical coherence tomography (OCT). This retrospective cross-sectional study included 690 eyes in 492 patients with OCT images and axial length measurement. Eyes were divided into three groups based on axial length: a “normal group,” a “high myopia group,” and an “other retinal disease” group. The researchers trained and validated three DL models to classify the three groups based on horizontal and vertical OCT images of the 600 eyes. For evaluation, OCT images of 90 eyes were used. Diagnostic agreements of human doctors and DL models were analyzed. The area under the receiver operating characteristic curve of the three DL models was evaluated. Absolute agreement of retina specialists was 99.11% (range: 97.78–100%). Absolute agreement of the DL models with multiple-column model was 100.0% (ResNet 50), 90.0% (Inception V3), and 72.22% (VGG 16). Areas under the receiver operating characteristic curves of the DL models with multiple-column model were 0.99 (ResNet 50), 0.97 (Inception V3), and 0.86 (VGG 16). The DL model based on ResNet 50 showed comparable diagnostic performance with retinal specialists. The DL model using OCT images demonstrated reliable diagnostic performance to identify high myopia.

Prospective cohort study to evaluate the accuracy of sleep measurement by consumer-grade smart devices compared with polysomnography in a sleep disorders population

ObjectivesConsumer-grade smart devices are now commonly used by the public to measure waking activity and sleep. However, the ability of these devices to accurately measure sleep in clinical populations warrants more examination. The aim of the present study was to assess the accuracy of three consumer-grade sleep monitors compared with gold standard polysomnography (PSG).DesignA prospective cohort study was performed.SettingAdults undergoing PSG for investigation of a suspected sleep disorder.Participants54 sleep-clinic patients were assessed using three consumer-grade sleep monitors (Jawbone UP3, ResMed S+ and Beddit) in addition to PSG.OutcomesJawbone UP3, ResMed S+ and Beddit were compared with gold standard in-laboratory PSG on four major sleep parameters—total sleep time (TST), sleep onset latency (SOL), wake after sleep onset (WASO) and sleep efficiency (SE).ResultsThe accelerometer Jawbone UP3 was found to overestimate TST by 28 min (limits of agreement, LOA=−100.23 to 157.37), with reasonable agreement compared with gold standard for TST, WASO and SE. The doppler radar ResMed S+ device underestimated TST by 34 min (LOA=−257.06 to 188.34) and had poor absolute agreement compared with PSG for TST, SOL and SE. The mattress device, Beddit underestimated TST by 53 min (LOA=−238.79 to 132) on average and poor reliability compared with PSG for all measures except TST. High device synchronisation failure occurred, with 20% of recordings incomplete due to Bluetooth drop out and recording loss.ConclusionPoor to moderate agreement was found between PSG and each of the tested devices, however, Jawbone UP3 had relatively better absolute agreement than other devices in sleep measurements compared with PSG. Consumer grade devices assessed do not have strong enough agreement with gold standard measurement to replace clinical evaluation and PSG sleep testing. The models tested here have been superseded and newer models may have increase accuracy and thus potentially powerful patient engagement tools for long-term sleep measurement.

An interrater reliability study on the Gothenburg obstetric triage system- a new obstetric triage system

Background Triage, identifying patients with critical and time-sensitive disorders, is an integrated process in general emergency medicine. Obstetric triage is more specialised, requiring assessment of both woman, fetus and labour status. Failure to identify severely ill obstetric patients has repeatedly led to maternal morbidity and mortality. Reliable triage systems, adapted to obstetric patients as well as local conditions, are thus essential. The study aims to assess the interrater reliability (IRR) of the Gothenburg Obstetric Triage System (GOTS). Methods Midwives (n = 6) and registered nurses with no experience in managing obstetric patients (n = 7), assessed 30 paper cases based on actual real-life cases, using the GOTS. Furthermore, a reference group consisting of two midwives and two obstetricians, with extensive experience in obstetric care, determined the correct triage level in order to enable analysis of over- and undertriage. IRR was assessed, both with percentage of absolute agreement and with intra-class correlation coefficients (ICC) with 95% confidence intervals (CI). Results A total of 388 assessments were performed, comprising all five levels of acuity in the GOTS. Absolute agreement was found in 69.6% of the assessments. The overall IRR was good, with a Kappa value of 0.78 (0.69–0.87, 95% CI) for final triage level. Comparison with reference group assessments established that over- and undertriage had occurred in 9% and 21% of the cases, respectively. The main reasons for undertriage were “not acknowledging abnormal vital sign parameters” and “limitations in study design”. Conclusion The GOTS is a reliable tool for triaging obstetric patients. It enables a standardized triage process unrelated to the assessors’ level of experience in assessing and managing obstetric patients and is applicable for triaging obstetric patients presenting for emergency care at obstetric or emergency units.

Reliability of the Preliminary OMERACT Juvenile Idiopathic Arthritis MRI Score (OMERACT JAMRIS-SIJ)

This study reports the reliability of the juvenile idiopathic arthritis magnetic resonance imaging scoring system (JAMRIS-SIJ). The study comprised of eight raters—two rheumatologists and six radiologists—and 30 coronal T1 and Short-Tau Inversion Recovery (STIR) MRI scans of patients with enthesitis-related juvenile spondylarthritis. The median age of patients was 15 years with a mean disease duration of 5 years and 22 (73.3%) of the sample were boys. The inter-rater agreement of scores for each of the JAMRIS-SIJ items was calculated using a two-way random effect, absolute agreement, and single rater intraclass correlation coefficient (ICC 2.1). The ICC was interpreted together with kurtosis, since the ICC is also affected by the distribution of scores in the sample. The eight-rater, single measure inter-rater ICC (and kurtosis) values for JAMRIS-SIJ inflammation and damage components were the following: bone marrow edema (BME), 0.76 (1.2); joint space inflammation, 0.60 (1.8); capsulitis, 0.58 (9.2); enthesitis, 0.20 (0.1); ankylosis, 0.89 (35); sclerosis, 0.53 (4.6); erosion, 0.50 (6.5); fat lesion, 0.40 (21); backfill, 0.38 (38). The inter-rater reliability for BME and ankylosis scores was good and met the a priori set ICC threshold, whereas for the other items it was variable and below the selected threshold. Future directives should focus on refinement of the scores, definitions, and methods of interpretation prior to validation of the JAMRIS-SIJ through the assessment of its measurement properties.

Wearable Inertial Gait Algorithms: Impact of Wear Location and Environment in Healthy and Parkinson’s Populations

Wearable inertial measurement units (IMUs) are used in gait analysis due to their discrete wearable attachment and long data recording possibilities within indoor and outdoor environments. Previously, lower back and shin/shank-based IMU algorithms detecting initial and final contact events (ICs-FCs) were developed and validated on a limited number of healthy young adults (YA), reporting that both IMU wear locations are suitable to use during indoor and outdoor gait analysis. However, the impact of age (e.g., older adults, OA), pathology (e.g., Parkinson′s Disease, PD) and/or environment (e.g., indoor vs. outdoor) on algorithm accuracy have not been fully investigated. Here, we examined IMU gait data from 128 participants (72-YA, 20-OA, and 36-PD) to thoroughly investigate the suitability of ICs-FCs detection algorithms (1 × lower back and 1 × shin/shank-based) for quantifying temporal gait characteristics depending on IMU wear location and walking environment. The level of agreement between algorithms was investigated for different cohorts and walking environments. Although mean temporal characteristics from both algorithms were significantly correlated for all groups and environments, subtle but characteristically nuanced differences were observed between cohorts and environments. The lowest absolute agreement level was observed in PD (ICC2,1 = 0.979, 0.806, 0.730, 0.980) whereas highest in YA (ICC2,1 = 0.987, 0.936, 0.909, 0.989) for mean stride, stance, swing, and step times, respectively. Absolute agreement during treadmill walking (ICC2,1 = 0.975, 0.914, 0.684, 0.945), indoor walking (ICC2,1 = 0.987, 0.936, 0.909, 0.989) and outdoor walking (ICC2,1 = 0.998, 0.940, 0.856, 0.998) was found for mean stride, stance, swing, and step times, respectively. Findings of this study suggest that agreements between algorithms are sensitive to the target cohort and environment. Therefore, researchers/clinicians should be cautious while interpreting temporal parameters that are extracted from inertial sensors-based algorithms especially for those with a neurological condition.

Knowledge of end-of-life wishes by physicians and family caregivers in cancer patients

Objectives To describe communication regarding cancer patient’s end-of-life (EoL) wishes by physicians and family caregivers. Methods An online questionnaire and telephone-based surveys were performed with physicians and family caregivers respectively in three teaching hospitals in Colombia which had been involved in the EoL care of cancer patients. Results For 138 deceased patients we obtained responses from physicians and family caregivers. In 32 % physicians reported they spoke to the caregiver and in 17 % with the patient regarding EoL decisions. In most cases lacking a conversation, physicians indicated the treatment option was “clearly the best for the patient” or that it was “not necessary to discuss treatment with the patient”. Twenty-six percent of the caregivers indicated that someone from the medical team spoke with the patient about treatment, and in 67% who had a conversation, caregivers felt that the provided information was unclear or incomplete. Physicians and family caregivers were aware if the patient had any advance care directive in 6% and 26% of cases, respectively, with low absolute agreement (34%). Conclusions There is a lack of open conversation regarding EoL in patients with advanced cancer with their physicians and family caregivers in Colombia. Communication strategies are urgently needed.

Differences Between MR Brain Region Segmentation Methods: Impact on Single-Subject Analysis

For the segmentation of magnetic resonance brain images into anatomical regions, numerous fully automated methods have been proposed and compared to reference segmentations obtained manually. However, systematic differences might exist between the resulting segmentations, depending on the segmentation method and underlying brain atlas. This potentially results in sensitivity differences to disease and can further complicate the comparison of individual patients to normative data. In this study, we aim to answer two research questions: 1) to what extent are methods interchangeable, as long as the same method is being used for computing normative volume distributions and patient-specific volumes? and 2) can different methods be used for computing normative volume distributions and assessing patient-specific volumes? To answer these questions, we compared volumes of six brain regions calculated by five state-of-the-art segmentation methods: Erasmus MC (EMC), FreeSurfer (FS), geodesic information flows (GIF), multi-atlas label propagation with expectation–maximization (MALP-EM), and model-based brain segmentation (MBS). We applied the methods on 988 non-demented (ND) subjects and computed the correlation (PCC-v) and absolute agreement (ICC-v) on the volumes. For most regions, the PCC-v was good (>0.75), indicating that volume differences between methods in ND subjects are mainly due to systematic differences. The ICC-v was generally lower, especially for the smaller regions, indicating that it is essential that the same method is used to generate normative and patient data. To evaluate the impact on single-subject analysis, we also applied the methods to 42 patients with Alzheimer’s disease (AD). In the case where the normative distributions and the patient-specific volumes were calculated by the same method, the patient’s distance to the normative distribution was assessed with the z-score. We determined the diagnostic value of this z-score, which showed to be consistent across methods. The absolute agreement on the AD patients’ z-scores was high for regions of thalamus and putamen. This is encouraging as it indicates that the studied methods are interchangeable for these regions. For regions such as the hippocampus, amygdala, caudate nucleus and accumbens, and globus pallidus, not all method combinations showed a high ICC-z. Whether two methods are indeed interchangeable should be confirmed for the specific application and dataset of interest.

Measuring Spatiotemporal Parameters on Treadmill Walking Using Wearable Inertial System

This study aims to measure and compare spatiotemporal gait parameters in nineteen subjects using a full wearable inertial mocap system Xsens (MVN Awinda, Netherlands) and a photoelectronic system one-meter OptoGaitTM (Microgait, Italy) on a treadmill imposing a walking speed of 5 km/h. A total of eleven steps were considered for each subject constituting a dataset of 209 samples from which spatiotemporal parameters (SPT) were calculated. The step length measurement was determined using two methods. The first one considers the calculation of step length based on the inverted pendulum model, while the second considers an anthropometric approach that correlates the stature with an anthropometric coefficient. Although the absolute agreement and consistency were found for the calculation of the stance phase, cadence and gait cycle, from our study, differences in SPT were found between the two systems. Mean square error (MSE) calculation of their speed (m/s) with respect to the imposed speed on a treadmill reveals a smaller error (MSE = 0.0008) using the OptoGaitTM. Overall, our results indicate that the accurate detection of heel strike and toe-off have an influence on phases and sub-phases for the entire acquisition. Future study in this domain should investigate how to design and integrate better products and algorithms aiming to solve the problematic issues already identified in this study without limiting the user’s need and performance in a different environment.

An Interrater Reliability Study on the Gothenburg Obstetric Triage System- a New Obstetric Triage System

Background Triage, identifying patients with critical and time-sensitive disorders, is an integrated process in general emergency medicine. Obstetric triage is more specialised, requiring assessment of both woman, fetus and labour status. Failure to identify severely ill obstetric patients has repeatedly led to maternal morbidity and mortality. Reliable triage systems, adapted to obstetric patients as well as local conditions, are thus essential. The study aims to assess the interrater reliability (IRR) of the Gothenburg Obstetric Triage System (GOTS). Methods Midwives (n=6) and registered nurses with no experience in managing obstetric patients (n=7), assessed 30 paper cases based on actual real-life cases, using the GOTS. Furthermore, a consensus group consisting of two midwives and two obstetricians, with extensive experience in obstetric care, determined the correct triage level in order to enable analysis of over- and undertriage. IRR was assessed, both with percentage of absolute agreement and with intra-class correlation coefficients (ICC) with 95% confidence intervals (CI). Results A total of 418 assessments were performed, comprising all five levels of acuity in the GOTS. Absolute agreement was found in 69.6% of the assessments. The overall IRR was good, with a Kappa value of 0.78 (0.69 – 0.87, 95% CI) for final triage level. Comparison with consensus group assessments established that over- and undertriage had occurred in 9% and 21% of the cases, respectively. The main reasons for undertriage were “not acknowledging abnormal vital sign parameters” and “limitations in study design”. Conclusion The GOTS is a reliable tool for triaging obstetric patients. It enables a standardized triage process unrelated to the assessors’ level of experience in assessing and managing obstetric patients and is applicable for triaging obstetric patients presenting for emergency care at obstetric or emergency units.