Real life clinical outcomes of relapsed/refractory diffuse large B cell lymphoma in the rituximab era: The STRIDER study.

BACKGROUND: Relapse and refractory (R/R) rates after first-line R-CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. AIMS: We conducted a retrospective real-world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. MATERIAL AND METHODS: Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. RESULTS: At a median follow up of 50 months, 5-year overall survival from diagnosis (OS-1) was 66.5%, and 2-year progression free survival (PFS-1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R-CHOP. Most employed salvage treatments included platinum salt-based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS-2 and PFS-2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS-2 or PFS-2 in patients treated with platinum-based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of <2 sites were associated with better OS-2. DISCUSSION: Our findings confirm very poor outcomes of R/R DLBCL in the rituximab era. Widespread approval by national Medicine Agencies of novel treatments such as CAR-T cells and bispecific antibodies as second-line is eagerly awaited to improve these outcomes.

A comparative study of muscle activity and synergies during walking in baboons and humans.

Bipedal locomotion was a major functional change during hominin evolution, yet, our understanding of this gradual and complex process remains strongly debated. Based on fossil discoveries, it is possible to address functional hypotheses related to bipedal anatomy, however, motor control remains intangible with this approach. Using comparative models which occasionally walk bipedally has proved to be relevant to shed light on the evolutionary transition toward habitual bipedalism. Here, we explored the organization of the neuromuscular control using surface electromyography (sEMG) for six extrinsic muscles in two baboon individuals when they walk quadrupedally and bipedally on the ground. We compared their muscular coordination to five human subjects walking bipedally. We extracted muscle synergies from the sEMG envelopes using the non-negative matrix factorization algorithm which allows decomposing the sEMG data in the linear combination of two non-negative matrixes (muscle weight vectors and activation coefficients). We calculated different parameters to estimate the complexity of the sEMG signals, the duration of the activation of the synergies, and the generalizability of the muscle synergy model across species and walking conditions. We found that the motor control strategy is less complex in baboons when they walk bipedally, with an increased muscular activity and muscle coactivation. When comparing the baboon bipedal and quadrupedal pattern of walking to human bipedalism, we observed that the baboon bipedal pattern of walking is closer to human bipedalism for both baboons, although substantial differences remain. Overall, our findings show that the muscle activity of a non-adapted biped effectively fulfills the basic mechanical requirements (propulsion and balance) for walking bipedally, but substantial refinements are possible to optimize the efficiency of bipedal locomotion. In the evolutionary context of an expanding reliance on bipedal behaviors, even minor morphological alterations, reducing muscle coactivation, could have faced strong selection pressure, ultimately driving bipedal evolution in hominins.

Balance and Muscle Synergies During a Single-Limb Stance Task in Individuals With Chronic Ankle Instability.

The aim of this study was to investigate balance performance and muscle synergies during a Single-Limb Stance (SLS) task in individuals with Chronic Ankle Instability (CAI) and a group of healthy controls. Twenty individuals with CAI and twenty healthy controls were asked to perform a 30-second SLS task in Open-Eyes (OE) and Closed-Eyes (CE) conditions while standing on a force platform with the injured or the dominant limb, respectively. The activation of 13 muscles of the lower limb, hip, and back was recorded by means of surface electromyography. Balance performance was assessed by identifying the number and the duration of SLS epochs, and the Root-Mean-Square (RMS) in Antero-Posterior (AP) and Medio-Lateral (ML) directions of the body-weight normalized ground reaction forces. The optimal number of synergies, weight vectors, and activation coefficients were also analyzed. CAI group showed a higher number and a shorter duration of SLS epochs and augmented ground reaction force RMS in both AP and ML directions compared to controls. Both groups showed an increase in the RMS in AP and ML forces in CE compared to OE. Both groups showed 4 optimal synergies in CE, while controls showed 5 synergies in OE. CAI showed a significantly higher weight of knee flexor muscles in both OE and CE. In conclusion, muscle synergies analysis provided an in-depth knowledge of motor control mechanisms in CAI individuals. They showed worse balance performance, a lower number of muscle synergies in a CE condition and abnormal knee flexor muscle activation compared to healthy controls.

Candidate germline biomarkers of lenalidomide efficacy in mantle cell lymphoma: the Fondazione Italiana Linfomi MCL0208 trial.

In the Fondazione Italiana Linfomi MCL0208 phase 3 trial, lenalidomide maintenance (LEN) after autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL) improved progression-free survival (PFS) vs observation (OBS). The host pharmacogenetic background was analyzed to decipher whether single-nucleotide polymorphisms (SNPs) of genes encoding transmembrane transporters, metabolic enzymes, or cell-surface receptors might predict drug efficacy. Genotypes were obtained via real-time polymerase chain reaction of the peripheral blood germ line DNA. Polymorphisms of ABCB1 and VEGF were found in 69% and 79% of 278 patients, respectively, and predicted favorable PFS vs homozygous wild-type (WT) in the LEN arm was 3-year PFS of 85% vs 70% (P < .05) and 85% vs 60% (P < .01), respectively. Patients carrying both ABCB1 and VEGF WT had the poorest 3-year PFS (46%) and overall survival (76%); in fact, in these patients, LEN did not improve PFS vs OBS (3-year PFS, 44% vs 60%; P = .62). Moreover, the CRBN polymorphism (n = 28) was associated with lenalidomide dose reduction or discontinuation. Finally, ABCB1, NCF4, and GSTP1 polymorphisms predicted lower hematological toxicity during induction, whereas ABCB1 and CRBN polymorphisms predicted lower risk of grade ≥3 infections. This study demonstrates that specific SNPs represent candidate predictive biomarkers of immunochemotherapy toxicity and LEN efficacy after ASCT in MCL.

Muscle synergies in Parkinson's disease before and after the deep brain stimulation of the bilateral subthalamic nucleus.

The aim of this study is to quantitatively assess motor control changes in Parkinson's disease (PD) patients after bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS), based on a novel muscle synergy evaluation approach. A group of 20 PD patients evaluated at baseline (before surgery, T0), at 3 months (T1), and at 12 months (T2) after STN-DBS surgery, as well as a group of 20 age-matched healthy control subjects, underwent an instrumented gait analysis, including surface electromyography recordings from 12 muscles. A smaller number of muscle synergies was found in PD patients (4 muscle synergies, at each time point) compared to control subjects (5 muscle synergies). The neuromuscular robustness of PD patients-that at T0 was smaller with respect to controls (PD T0: 69.3 ± 2.2% vs. Controls: 77.6 ± 1.8%, p = 0.004)-increased at T1 (75.8 ± 1.8%), becoming not different from that of controls at T2 (77.5 ± 1.9%). The muscle synergies analysis may offer clinicians new knowledge on the neuromuscular structure underlying PD motor types of behavior and how they can improve after electroceutical STN-DBS therapy.

Punctual and kinetic MRD analysis from the Fondazione Italiana Linfomi MCL0208 phase 3 trial in mantle cell lymphoma.

Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood [PB] and bone marrow [BM]), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction [RQ-PCR]). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression [TTP] hazard ratio [HR], 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).

Evaluation of Muscle Function by Means of a Muscle-Specific and a Global Index.

Gait analysis applications in clinics are still uncommon, for three main reasons: (1) the considerable time needed to prepare the subject for the examination; (2) the lack of user-independent tools; (3) the large variability of muscle activation patterns observed in healthy and pathological subjects. Numerical indices quantifying the muscle coordination of a subject could enable clinicians to identify patterns that deviate from those of a reference population and to follow the progress of the subject after surgery or completing a rehabilitation program. In this work, we present two user-independent indices. First, a muscle-specific index (MFI) that quantifies the similarity of the activation pattern of a muscle of a specific subject with that of a reference population. Second, a global index (GFI) that provides a score of the overall activation of a muscle set. These two indices were tested on two groups of healthy and pathological children with encouraging results. Hence, the two indices will allow clinicians to assess the muscle activation, identifying muscles showing an abnormal activation pattern, and associate a functional score to every single muscle as well as to the entire muscle set. These opportunities could contribute to facilitating the diffusion of surface EMG analysis in clinics.

Long short-term memory (LSTM) recurrent neural network for muscle activity detection.

BACKGROUND: The accurate temporal analysis of muscle activation is of great interest in many research areas, spanning from neurorobotic systems to the assessment of altered locomotion patterns in orthopedic and neurological patients and the monitoring of their motor rehabilitation. The performance of the existing muscle activity detectors is strongly affected by both the SNR of the surface electromyography (sEMG) signals and the set of features used to detect the activation intervals. This work aims at introducing and validating a powerful approach to detect muscle activation intervals from sEMG signals, based on long short-term memory (LSTM) recurrent neural networks. METHODS: First, the applicability of the proposed LSTM-based muscle activity detector (LSTM-MAD) is studied through simulated sEMG signals, comparing the LSTM-MAD performance against other two widely used approaches, i.e., the standard approach based on Teager-Kaiser Energy Operator (TKEO) and the traditional approach, used in clinical gait analysis, based on a double-threshold statistical detector (Stat). Second, the effect of the Signal-to-Noise Ratio (SNR) on the performance of the LSTM-MAD is assessed considering simulated signals with nine different SNR values. Finally, the newly introduced approach is validated on real sEMG signals, acquired during both physiological and pathological gait. Electromyography recordings from a total of 20 subjects (8 healthy individuals, 6 orthopedic patients, and 6 neurological patients) were included in the analysis. RESULTS: The proposed algorithm overcomes the main limitations of the other tested approaches and it works directly on sEMG signals, without the need for background-noise and SNR estimation (as in Stat). Results demonstrate that LSTM-MAD outperforms the other approaches, revealing higher values of F1-score (F1-score > 0.91) and Jaccard similarity index (Jaccard > 0.85), and lower values of onset/offset bias (average absolute bias < 6 ms), both on simulated and real sEMG signals. Moreover, the advantages of using the LSTM-MAD algorithm are particularly evident for signals featuring a low to medium SNR. CONCLUSIONS: The presented approach LSTM-MAD revealed excellent performances against TKEO and Stat. The validation carried out both on simulated and real signals, considering normal as well as pathological motor function during locomotion, demonstrated that it can be considered a powerful tool in the accurate and effective recognition/distinction of muscle activity from background noise in sEMG signals.

Muscle activations during functional tasks in individuals with chronic ankle instability: a systematic review of electromyographical studies.

BACKGROUND: It has been reported that individuals with chronic ankle instability (CAI) show motor control abnormalities. The study of muscle activations by means of surface electromyography (sEMG) plays a key role in understanding some of the features of movement abnormalities. RESEARCH QUESTION: Do common sEMG activation abnormalities and strategies exists across different functional movements? METHODS: Literature review was conducted on PubMed, Web-of-Science and Cochrane databases. Studies published between 2000 and 2020 that assessed muscle activations by means of sEMG during any type of functional task in individuals with CAI, and used healthy individuals as controls, were included. Methodological quality was assessed using the modified Downs&Black checklist. Since the methodologies of different studies were heterogeneous, no meta-analysis was conducted. RESULTS: A total of 63 articles investigating muscle activations during gait, running, responses to perturbations, landing and hopping, cutting and turning; single-limb stance, star excursion balance task, forward lunges, ball-kicking, y-balance test and single-limb squatting were considered. Individuals with CAI showed a delayed activation of the peroneus longus in response to sudden inversion perturbations, in transitions between double- and single-limb stance, and in landing on unstable surfaces. Apparently, while walking on ground there are no differences between CAI and controls, walking on a treadmill increases the variability of muscles activations, probably as a "safety strategy" to avoid ankle inversion. An abnormal activation of the tibialis anterior was observed during a number of tasks. Finally, hip/spine muscles were activated before ankle muscles in CAI compared to controls. CONCLUSION: Though the methodology of the studies herein considered is heterogeneous, this review shows that the peroneal and tibialis anterior muscles have an abnormal activation in CAI individuals. These individuals also show a proximal muscle activation strategy during the performance of balance challenging tasks. Future studies should investigate whole-body muscle activation abnormalities in CAI individuals.

Atypical Gait Cycles in Parkinson's Disease.

It is important to find objective biomarkers for evaluating gait in Parkinson's Disease (PD), especially related to the foot and lower leg segments. Foot-switch signals, analyzed through Statistical Gait Analysis (SGA), allow the foot-floor contact sequence to be characterized during a walking session lasting five-minutes, which includes turnings. Gait parameters were compared between 20 PD patients and 20 age-matched controls. PDs showed similar straight-line speed, cadence, and double-support compared to controls, as well as typical gait-phase durations, except for a small decrease in the flat-foot contact duration (-4% of the gait cycle, p = 0.04). However, they showed a significant increase in atypical gait cycles (+42%, p = 0.006), during both walking straight and turning. A forefoot strike, instead of a "normal" heel strike, characterized the large majority of PD's atypical cycles, whose total percentage was 25.4% on the most-affected and 15.5% on the least-affected side. Moreover, we found a strong correlation between the atypical cycles and the motor clinical score UPDRS-III (r = 0.91, p = 0.002), in the subset of PD patients showing an abnormal number of atypical cycles, while we found a moderate correlation (r = 0.60, p = 0.005), considering the whole PD population. Atypical cycles have proved to be a valid biomarker to quantify subtle gait dysfunctions in PD patients.

An Algorithm for Choosing the Optimal Number of Muscle Synergies during Walking.

In motor control studies, the 90% thresholding of variance accounted for (VAF) is the classical way of selecting the number of muscle synergies expressed during a motor task. However, the adoption of an arbitrary cut-off has evident drawbacks. The aim of this work is to describe and validate an algorithm for choosing the optimal number of muscle synergies (ChoOSyn), which can overcome the limitations of VAF-based methods. The proposed algorithm is built considering the following principles: (1) muscle synergies should be highly consistent during the various motor task epochs (i.e., remaining stable in time), (2) muscle synergies should constitute a base with low intra-level similarity (i.e., to obtain information-rich synergies, avoiding redundancy). The algorithm performances were evaluated against traditional approaches (threshold-VAF at 90% and 95%, elbow-VAF and plateau-VAF), using both a simulated dataset and a real dataset of 20 subjects. The performance evaluation was carried out by analyzing muscle synergies extracted from surface electromyographic (sEMG) signals collected during walking tasks lasting 5 min. On the simulated dataset, ChoOSyn showed comparable performances compared to VAF-based methods, while, in the real dataset, it clearly outperformed the other methods, in terms of the fraction of correct classifications, mean error (ME), and root mean square error (RMSE). The proposed approach may be beneficial to standardize the selection of the number of muscle synergies between different research laboratories, independent of arbitrary thresholds.

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial.

BACKGROUND: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). METHODS: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0-9.6; High→Int, HR: 2.3, 95% CI: 1.5-4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential.

Surface Electromyography Applied to Gait Analysis: How to Improve Its Impact in Clinics?

Surface electromyography (sEMG) is the main non-invasive tool used to record the electrical activity of muscles during dynamic tasks. In clinical gait analysis, a number of techniques have been developed to obtain and interpret the muscle activation patterns of patients showing altered locomotion. However, the body of knowledge described in these studies is very seldom translated into routine clinical practice. The aim of this work is to analyze critically the key factors limiting the extensive use of these powerful techniques among clinicians. A thorough understanding of these limiting factors will provide an important opportunity to overcome limitations through specific actions, and advance toward an evidence-based approach to rehabilitation based on objective findings and measurements.

Muscle Synergy Assessment During Single-Leg Stance.

In the study of muscle synergies during the maintenance of single-leg stance there are several methodological issues that must be taken into account before muscle synergy extraction. In particular, it is important to distinguish between epochs of surface electromyography (sEMG) signals corresponding to "well-balanced" and "unbalanced" single-leg stance, since different motor control strategies could be used to maintain balance. The aim of this work is to present and define a robust procedure to distinguish between "well-balanced" and "unbalanced" single-leg stance to be chosen as input for the algorithm used to extract muscle synergies. Our results demonstrate that the proposed approach for the selection of sEMG epochs relative to "well-balanced" and "unbalanced" single-leg stance is robust with respect to the selection of the segmentation threshold, revealing a high consistency in the number of muscle synergies and high similarity among the weight vectors (correlation values range from 0.75 to 0.97). Moreover, differences in terms of average recruitment levels and balance control strategies were detected, suggesting a slightly different modular organization between "well-balanced" and "unbalanced" single-leg stance. In conclusion, this approach can be successfully used as a pre-processing step before muscle synergy extraction, allowing for a better assessment of motor control strategies during the single-leg stance task.

Muscle Synergies Extracted Using Principal Activations: Improvement of Robustness and Interpretability.

The muscle synergy theory has been widely used to assess the modular organization of the central nervous system (CNS) during human locomotion. The pre-processing approach applied to the surface electromyographic (sEMG) signals influences the extraction of muscle synergies. The aim of this contribution is to assess the improvements in muscle synergy extraction obtained by using an innovative pre-processing approach. We evaluate the improvement in terms of the possible variation in the number of muscle synergies, of the intra-subject consistency, of the robustness, and of the interpretability of the results. The pre-processing approach presented in this paper is based on the extraction of the muscle principal activations (muscle activations strictly necessary to accomplish a specific biomechanical task) from the original sEMG signals, to then obtain muscle synergies using principal activations only. The results herein presented show that the application of this novel approach for the extraction of the muscle synergies provides a more robust and easily interpretable description of the modular organization of the CNS with respect to the standard pre-processing approach.

Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.

PURPOSE: Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. METHODS: Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. RESULTS: The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. CONCLUSION: The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.

Wearable Inertial Sensors to Assess Standing Balance: A Systematic Review.

Wearable sensors are de facto revolutionizing the assessment of standing balance. The aim of this work is to review the state-of-the-art literature that adopts this new posturographic paradigm, i.e., to analyse human postural sway through inertial sensors directly worn on the subject body. After a systematic search on PubMed and Scopus databases, two raters evaluated the quality of 73 full-text articles, selecting 47 high-quality contributions. A good inter-rater reliability was obtained (Cohen's kappa = 0.79). This selection of papers was used to summarize the available knowledge on the types of sensors used and their positioning, the data acquisition protocols and the main applications in this field (e.g., "active aging", biofeedback-based rehabilitation for fall prevention, and the management of Parkinson's disease and other balance-related pathologies), as well as the most adopted outcome measures. A critical discussion on the validation of wearable systems against gold standards is also presented.

Feasibility of Muscle Synergy Outcomes in Clinics, Robotics, and Sports: A Systematic Review.

In the last years, several studies have been focused on understanding how the central nervous system controls muscles to perform a specific motor task. Although it still remains an open question, muscle synergies have come to be an appealing theory to explain the modular organization of the central nervous system. Even though the neural encoding of muscle synergies remains controversial, a large number of papers demonstrated that muscle synergies are robust across different tested conditions, which are within a day, between days, within a single subject, and between subjects that have similar demographic characteristics. Thus, muscle synergy theory has been largely used in several research fields, such as clinics, robotics, and sports. The present systematical review aims at providing an overview on the applications of muscle synergy theory in clinics, robotics, and sports; in particular, the review is focused on the papers that provide tangible information for (i) diagnosis or pathology assessment in clinics, (ii) robot-control design in robotics, and (iii) athletes' performance assessment or training guidelines in sports.