PMID_x
stringlengths 4
15
| PMCID_x
stringlengths 4
12
| RefID
stringlengths 2
4.63k
| paragraph
stringlengths 1
44.2k
⌀ | AccessionID
stringlengths 10
11
| subjects
stringlengths 3
3.86k
| keywords
float64 | PMID_y
int64 27M
37.9M
| Title
stringlengths 16
441
| Authors
stringlengths 5
1.2k
| Citation
stringlengths 36
124
| First Author
stringlengths 3
126
| Journal/Book
stringlengths 3
42
| Publication Year
int64 2.02k
2.03k
| Create Date
stringlengths 10
10
| PMCID_y
stringlengths 10
11
| NIHMS ID
stringclasses 335
values | DOI
stringlengths 13
44
⌀ | Key
stringlengths 30
31
| ETag
stringlengths 32
32
| Article Citation
stringlengths 16
71
| Last Updated UTC (YYYY-MM-DD HH:MM:SS)
stringlengths 19
19
| License
stringclasses 2
values | Retracted
stringclasses 2
values |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
['PMC8080700'] | ['33911100'] | ['Tab6'] | Post-stroke recovery is a complex process and can be viewed from different aspects (impairments, activity, and participation) according to the International Classification of Functioning, Disability and Health (ICF). Therefore, it could be of interest to test for potential patterns of relationships between impairments (range of motion, strength, tone, EMG parameters) and function (BBT and Barthel Index) from an ICF perspective. Accordingly, and as additional analyses, zero-order correlations were calculated among the 11 measures of motor impairment and the two functional outcome measures (BBT and Barthel Index), both in T1 (baseline) and T4 (follow-up). Correlations are shown in Table6. There are a number of significant correlations among motor impairment and functional variables. In general, the correlations were much larger and consistent in Time 4.Table 6Correlations among the motor impairment variables and the functional outcome measures.VariableBBTBarthel IndexTime 1Time 4Time 1Time 4Wrist resting angle0.2040.349**0.0830.266*Wrist active extension0.710**0.492**0.420**0.652**Wrist passive extension0.1970.1900.0860.436**MCP resting angle0.1950.2160.0980.251MCP active extension0.318*0.357**0.369**0.592**Grip strength0.541**0.473**0.1720.429**Pinch strength0.557**0.533**0.313*0.477**MAS score for wrist flexors− 0.219− 0.321*− 0.150− 0.345**MAS score for MCP flexors− 0.366**− 0.388**− 0.187− 0.395**Peak EMG amplitude extensors0.501**0.414**0.1850.432**ACR extensors− 0.170− 0.353**− 0.116− 0.516***p < .05; ** p < .01;BBTBox and Block Test,MCPMetacarpophalangeal;MASModified Ashworth Scale,ACRCo-activation ratio of the antagonist. | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8080700'] | ['33911100'] | [] | This trial may have two important contributions. On the one hand, it offers evidence of positive effects of NMES on motor recovery in older adults after stroke. On the other hand, NMES treatments with different frequency stimulation parameters were compared, which provided additional insights related to the optimisation of the applied protocol. Regarding the effect of NMES intervention, variables related to hand motor impairment were studied, such as range of motion, hand strength, muscle tone, and muscle electrical activity. Both protocols applied produced improvements in wrist and finger joint movements. Evidence from this study is similar to that of the great majority of authors who have evaluated this outcome measure30–35. In contrast, there are also studies36,37, which were directed towards patients in the acute phase, that did not show significant findings. Considering the positive results demonstrated in various studies with very different NMES protocols, the stimulation parameters may not be crucial for range of motion gain, although the results of this research showed that the 35 Hz protocol had a larger effect on range of motion when it was compared with the 50 Hz NMES treatment. Both studied protocols promoted improvements in the grip and pinch strength, although the 50 Hz NMES treatment had slightly larger effects than the 35 Hz NMES. These findings agree with the results of other authors14,27,34,37,38. Most of these studies mentioned selected patients with distal movement in the wrist or fingers. Referring to this point, Doucet and Griffin demonstrated differences according to the sample selected, where only patients with a high level of functionality showed changes27. In addition, these authors pointed out that a NMES group that used a stimulation frequency of 40 Hz showed significant improvements compared with a 20 Hz NMES group, concluding that higher frequencies could be more effective in improving strength. Previous studies also noted an increase in force production linked to the increase in NMES frequency. In this regard, Dreibati et al.39showed that NMES of the quadriceps femoris muscle in healthy adults represented respectively 71, 62, 55% of maximum voluntary contraction force for stimulation frequencies of 100, 50 and 20 Hz. Increases in muscle strength through NMES programmes would require the maintenance of 60% maximum voluntary contraction39. On the other hand, studies such as those by Powell et al.36and Chan et al.33revealed no significant findings for hand strength when NMES was applied. Powell et al.36pointed out that although a significant effect was not found, patients with a residual motor function showed better results. It should also be noted that the frequency used in this NMES protocol was 20 Hz, which could be a value with worse results in relation to strength, as concluded by Doucet and Griffin27. The study by Chan et al.33addressed patients without residual distal movement and in the chronic phase. Moreover, the total dose of electrostimulation was very low in comparison with other studies (5 h), factors which could have a bearing on the lack of results. Having appraised the results of the different trials, it would seem that low stimulation frequencies around 20 Hz could be less efficient in improving strength, and also that sample characteristics related to the presence of residual distal movement could influence the effectiveness of the treatment. Considering the MAS scale, both NMES protocols were shown to be effective in improving distal muscle tone in the upper limb, although the 35 Hz protocol had a larger effect when it was compared with the 50 Hz intervention. This effectiveness has also been reported by other authors30,34,40. However, there are also studies which failed to do so, such as those by Chan et al.33and Powell et al.36, the features of which have already been mentioned. Both NMES interventions were shown to improve muscle electrical activity in the wrist extensors, both in maximum activity and in the pattern of activation as antagonist. The few studies published in which EMG activity has been analysed34, used different EMG data collection protocols and although indications of improvement in muscle electrical activity were shown, comparison and the extraction of conclusive data on this point prove difficult. Doucet and Griffin studied the parameter of root mean square amplitude in the thumb adductor and obtained significant improvements in the group with high functionality and a greater effect with the NMES protocol which applied the stimulation frequency of 40 Hz compared to 20 Hz27. Some relationship was noted between change in co-activation and MAS scores, which could explain that improvements in muscle tone could also be associated to changes in neuromuscular control. Post-stroke recovery is a complex process that needs to be addressed on different aspects (impairments, activity, and participation) according to the ICF. Different studies stated that recovery at the impairment and body structure levels constitutes the basis to further recovery of activity domain of the ICF classification41–43. Given the results obtained, we consider carrying out subsequent correlational analysis to elucidate if there was a pattern of relationships between impairments (range of motion, hand strength, tone, and EMG activity) and function (BBT and Barthel Index) from an ICF perspective. Regarding functional measures, gains were evident only in the independence in activities of daily living (ADL), in favour of the 35 Hz NMES group. The results of this study showed that all three groups improved in manual dexterity, but although this improvement was greater in the experimental groups, these differences were not significant. The minimal clinically important difference (MICD) found in the literature of the Box and Block Test was 6 blocks/min for the more affected hand44. In our study the difference in manual dexterity did not show statistically significant differences between the groups because the three groups showed improvement. However, if we attend to the changes at MCID level, only the 35 Hz NMES group and the 50 Hz NMES group exceeded the MICD in the follow-up period (7.85 blocks and 8.55 blocks, respectively). The motor characteristics of the sample could have influenced these results. Alon et al. carried out two similar studies whose samples had different degrees of motor performance at the upper limb level7,45. Manual dexterity only improved in the study in which NMES intervention was applied in a sample with mild/moderate paresis7. This idea is also supported by Knutson et al. who indicated that the magnitudes of improvement were greater in participants with moderate hand impairment at baseline and a post-stroke period more than 6 months but less than 2 years of evolution46. Moreover, perhaps a longer duration of the treatment would have influenced the functional motor ability improvement, given the strong relationship between motor impairments and manual dexterity, as can be see in zero-order correlation analyses. In this regard, it has been hypothesized that 5 months would be necessary for an effective NMES intervention to improve upper limb function47. Although a NMES protocol with active participation of the subjects was proposed, more cognitive effort and goal-driven functional tasks could have also influenced the results, since they are elements that could be crucial in promoting neuroplasticity and achieving functional results17. Finally, the stimulation frequency could also have an impact on function. In relation to this, Doucet and Griffin only found improvement in manual dexterity in the high functioning group (Fugl-Meyer Motor Assessment score greater than 60) and with low frequency stimulation programmes around 20 Hz27. Subsequent analyses were carried out to determine which of the improved impairments best explained changes in Barthel Index. In general, the correlations were much larger and consistent in the follow-up period (T4) when they were compared with baseline (T1), which is reasonable given that most motor impairment measures improved with NMES and therefore there was more variability in the sample. The motor impairments that at baseline did not show significant correlations, but that at the end of the study presented associations with the Barthel Index were wrist resting angle, wrist passive extension for range of motion, grip strength, MAS, and EMG activity variables. This study is the first randomised clinical trial (RCT) of this nature aimed at older adults. The NMES protocols proposed show evidence of improvements in this subpopulation, but it remains unknown whether individuals of another age range would have responded in the same way to the treatment. Aging produces a series of changes associated with the central nervous system and the musculoskeletal system48, among others, which could condition a specific response to NMES intervention. The RCTs reviewed present heterogeneous samples and there is a lack of studies investigating the older population, or analyzing results according to age. Doucet and Griffin showed that there are differences in muscle response according to the different stimulation patterns during fatigue NMES protocols that could be related to changes in the neuromuscular system caused by central paralysis and age28. In addition, they pointed out the need to define specific stimulation parameters that maximise force output and delay the onset of fatigue in the clinical applications of NMES in the post-stroke population28. The optimum stimulation parameters are currently unknown17. Research indicated that frequency (number of pulses per second) affect force and fatigue development and that there is difference between muscles of different fibre composition (type I and type II fibres) and size, being necessary to adjust this parameter in each NMES programme49. In the present study, two NMES treatments with different stimulation frequency were compared. Both NMES protocols showed evidence of improvements in motor impairment variables, although the 35 Hz intervention had larger effects on range of motion, muscle tone and peak EMG amplitude of wrist extensors; and the 50 Hz NMES intervention had a larger effect on hand strength and the ACR of wrist extensors. With regard to the functional measures, only 35 Hz NMES intervention proved to be effective in functional independence in ADL. No significant gain between-groups was obtained related to manual dexterity. Only two articles have been found which study in depth this parameter; thus Doucet and Griffin showed that stimulation programmes that included higher frequencies around 40 Hz and varying pulse patterns were more effective in maximizing force output than lower frequencies around 20 Hz constant-pattern stimulation programmes28. The same authors later published another study in which the muscles of the thenar eminence were stimulated with the aim of investigating fine motor control, comparing protocols with frequencies of 20 Hz versus 40 Hz27. These authors concluded that the specific stimulation frequencies selected may have a direct impact on skills gained. Their results suggested that stimulation frequencies in the region of 40 Hz might be more effective for improving strength and motor activation properties, while lower levels around 20 Hz could have a greater impact on manual dexterity and muscular endurance27. In addition, the frequency could be related to particular patterns of muscle fibre activation. Frequencies below 40–50 Hz recruited more slow-twitch (type I fibres), while higher frequencies recruited more fast-twitch (type IIa and IIb fibres)39. Spasticity, lack of activity and disuse following stroke produce adaptive changes in the anatomy, biomechanics, and functionality of the nervous and musculoskeletal systems. Among these changes, Edstrom et al.50and Dattola et al.51made reference to modifications in the type of muscle fibre, characterized by a greater predominance of type I fibres and reduction in the proportion of type II fibres, a change also contributed to by aging29,48. These type I muscle fibres could have a greater affinity for stimulation frequencies below 40–50 Hz39. A current study concluded that if the main function of the muscle is related to sustained repetition of fine motor movements, lower-moderate NMES frequencies are preferred. By contrast, muscle functions related to force generation would require higher frequencies to achieve force production near of 60% maximum voluntary contraction49. Further research is needed to study this subject in depth to provide more solid data. Despite the fact that the design of this study is an RCT, certain limitations must be borne in mind such as the lack of blinding of the physical therapists who applied the treatment and of the assessor, the relatively short follow-up period, the retrospective registration of the RCT, and the difficulties in extrapolating results to other age groups. In addition, peak amplitude used as an EMG parameter is a measure than could be biased by the noise level. Advances in neuroscience and new technologies may possibly give rise to new applications of NMES for upper limb recovery after stroke, but future NMES protocols should take into account whether the basic programming parameters of the equipment are clinically relevant. More research is needed to elucidate the specific mechanism of action associated with the different stimulation parameters in order to guide clinical decisions. Elements such as motor characteristics of the subject, treatment dose, stage after stroke, cognitive effort, goal-driven functional tasks, and a proper selection of stimulation frequency according to the specific deficits should be addressed in the design of a NMES protocol. Future studies should analyse these aspects in depth in order to adapt treatment resources to the needs of each patient, and subsequently to optimise individual interventions and to achieve larger treatment effects. In conclusion, the NMES intervention could be a useful complementary treatment for upper limb motor recovery in older adults with spastic hemiparesis following stroke. Both NMES protocols showed evidence of improvements in measurements related to hand motor impairment, but nevertheless, effect sizes revealed different importance in range of motion, hand strength, muscle tone, and muscle electrical activity of the wrist extensors. Regarding functional improvements, only a superior effect for the 35 Hz NMES protocol in functional independence was found. These findings showed that the stimulation frequency selected could have different effects depending on skill under study. | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8080700'] | ['33911100'] | ['Fig1', 'Tab7'] | This study was a single-blind RCT where the participants were blind to group assignment. Participants were randomly assigned to the three groups: two experimental groups (50 Hz NMES and 35 Hz NMES) and a control group. A statistician not involved with the intervention or data collection performed the random allocation sequence (random number generator of SPSS 22). There were no restrictions in the randomisation. A priori power analyses were performed and the sample size needed for a power of .85, with the usual alpha of .05, and an effect size of d =1 as estimated in the meta-analysis by Pomeroy et al.24was 20 subjects per group. The study was approved by the Scientific and the Ethics Committee for Clinical Research of the Doctor Peset University Hospital of Valencia, Spain (CC 43/09) and was registered in the ClinicalTrials.gov (identifier NCT03913624; 12/04/2019). This study was retrospectively registered given that when the experiment was being performed pre-registration was not mandatory. The procedures were conducted according to the Declaration of Helsinki. All participants in the research were informed and signed informed consent prior to study participation. The Consolidated Standards of Reporting Trials (CONSORT) checklist was used to report the RCT. Participants were recruited from the aforementioned hospital, who attended for physical therapy intervention as outpatients between July 2009 and September 2014. A total of 262 older adults affected by spastic hemiparesis of the hand after stroke were screened for study eligibility. Of these, 69 individuals were scheduled for a baseline assessment. A flow diagram describes the participant eligibility and randomisation of the selected participants (see Fig.1). The inclusion criteria were presence of spastic hemiparesis caused by stroke (diagnosed by neuroimaging tests), a score ≤ 3 on the MAS for wrist and finger flexors, residual voluntary movement of wrist (active wrist extension ≥ 5° from the resting position) , wrist extension response to stimulation, age ≥ 60 years, post-stroke period < 18 months, clinical stability, and MMSE score ≥ 23 with the absence of significant cognitive impairment, being able to follow basic instructions and to collaborate in the treatment. The spasticity assessment included the Tardieu Scale and hyperreflexia of the deep tendon reflexes. Exclusion criteria comprised those situations that could alter the results or posed a risk for the patient. Table7displays the exclusion criteria taken into account in the study.Table 7Exclusion criteria.Dermatological reactions with the application of stimulationSignificant sensory deficits in the affected armPrevious musculoskeletal problems of the handTreatment with the botulin toxinAnti-spastic medication usageCardiac pacemaker, implanted electronic device, or metal implants in the affected armComplex regional pain syndromeSevere aphasia, history of epileptic seizures, psychiatric disorder, or important alterations of behaviorSevere visual impairmentAny comorbid neurological diseaseImportant deformity or obesity that affects the application of the NMESPotentially fatal cardiac arrhythmia or other descompensated heart diseaseSystemic infectious process, cancer, or other terminal disease | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8080700'] | ['33911100'] | [] | Shoulder motor control was measured with a reduced version of the MESUPES-arm test subscale within the Motor Evaluation Scale for Upper Extremity in Stroke patients52. A universal goniometer was used to measure the resting angle, active extension and passive extension of the wrist (°), and a special JAMAR finger goniometer to evaluate the resting angle and active extension of the MCP of the fingers (°). The grip strength was assessed by means of a standardised hydraulic hand dynamometer (JAMAR brand, model 5030J1, Sammons and Preston INC) and the pinch strength using a standardised hydraulic pinch gauge (JAMAR brand, model 7498-05, Sammons and Preston INC). Unit of measurement was kgf. Three repetitions were done in both evaluations, taking the highest value and leaving a resting period of 1 min between them. Muscle tone of the wrist flexors and the MCP flexors of the fingers was measured using MAS53,54. The assessment was started 5 min after laying the subject down in the supine position54and using a single passive movement to evaluate each muscle group55. Joints were moved from maximum possible flexion to maximum possible extension over a duration of about 1 s by counting one thousand one53,54,56to standardise the speed of the movement being tested. EMG activity was recorded in the radial extensor and the radial flexor of the carpus using the Muscle Trainer (model METR-0, Mega Electronics Ltd, Kuopio, Finland) and circular adhesive surface bipolar electrodes of Ag/AgCl (Ambú Blue Sensor, diameter 10mm). EMG preamplifier measurement sensitivity is ± 1 µV. The measurement range for RMS EMG signals was 0–4095 µV. AD-transformer for each EMG channel was carried out with an accuracy of 12 bits. Data memory was 32 kB. Signals were band-pass filtered at 20–500 Hz. Data was transferred from the receiver to a personal computer and analysed using MegaWin v.2.0 (Mega Electronics Ltd, Kuopio, Finland). The patient was asked to perform maximum voluntary isometric contractions (MVICs) of both the flexors and extensors of the wrist for 5 s against manual resistance, and the electrical activity of both the agonist and antagonist muscles was recorded simultaneously. EMG parameters were calculated related to the peak amplitude (in µV) and the antagonist co-activation ratio (ACR) calculated during MVICs of the wrist flexors (ACR = antagonist activity/ [agonist activity + antagonist activity] × 100%)57. ACR provides an estimate of the relative activation of the agonist-antagonist muscle pair and the magnitude of the co-activation of the antagonist. The average amplitude of the extensors was considered as the antagonist activity (µV) and the average amplitude of the flexors was considered as the agonist activity (µV). Manual dexterity was assessed with BBT58scored by counting the number of blocks moved by the affected side from one compartment of a box to another within 1-min trial period, and functional independence in ADL by Barthel Index59. There were four measurements over time: pre-treatment (T1), one month from the beginning of the study (T2), two months from the beginning of the study (end of treatment) (T3), and three months from the beginning of the study (follow-up) (T4). The second and third assessments were performed within 48 and 72 h after the last application of electrostimulation and were always recorded in the morning, in the same order and by the same examiner. | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8080700'] | ['33911100'] | [] | During an 8-week intervention period, training was conducted for 3 days per week (a total of 24 sessions). The two experimental groups received the conventional treatment (the same as the control group) for the same amount of time, plus NMES. The NMES application time was 20 min for the first 2 sessions and 30 min for subsequent sessions. Each NMES session took place under the supervision of an experienced physical therapist. 50 Hz NMES group: NMES was applied on wrist and finger extensors. The main electrostimulation parameters consisted of low-frequency current, a stimulation frequency of 50 Hz, symmetrical rectangular biphasic wave, and pulse duration of 300 μs. 35 Hz NMES group: NMES was applied on wrist and finger extensors. The main electrostimulation parameters consisted of low-frequency current, a stimulation frequency of 35 Hz, symmetrical rectangular biphasic wave, and pulse duration of 300 μs. The electrostimulation programmes were only differentiated in the parameter of the stimulation frequency, 35 Hz or 50 Hz, depending on the experimental group to which the patient belonged. The rest of the parameters were the same. The intensity was adjusted in order to allow a maximum extension of wrist and fingers ensuring the patient's comfort. Ramping up/down periods were established at a time of 2 s during the first week, and 1 s for the rest of the study. The contraction-relaxation times were adjusted during the treatment period (5–25 s in the first 2 weeks, 5–20 s in the third week, 5–15 s in the fourth week, 5–10 s during fifth to sixth weeks, and 5–5 s in final weeks). These parameters were modified during the treatment in order to adapt the training progressively and avoid muscle fatigue60,61. The application time was 20 min for the first two sessions and 30 min for subsequent sessions. Three sessions per week were conducted for a period of 8 weeks. Additionally, the patient was asked to actively participate by means of a voluntary contraction on feeling the stimulus and visualizing the movement. The electrodes were placed over the extensor muscles of the wrist and fingers, stimulating mainly the extensor carpi radialis longus and brevis, and the extensor digitorum communis. A line of the humeral epicondyle was drawn on the posterior part of the forearm to the midpoint of the wrist joint, and this was divided into three parts, placing one electrode approximately in the proximal third of this described line, and the other electrode in the distal third towards the posterolateral side of the forearm. A good extensor response was sought and the individual placement was recorded by means of a metric tape for later reproduction. The participant was placed in a sitting position (shoulder abduction of 0–30°, elbow flexion of 70–90°, pronated forearm, with a towel at the distal level of the forearm to start with a slight wrist flexion)62. For the application of the NMES, a portable apparatus (Beac Medical IntelliSTIM®BE 28-E) and disposable self-adhesive surface electrodes (En-Trode®50 × 50 mm) were used. The application of the NMES was tested to rule out any abnormal reaction to the passage of current or to the material used. The state of the skin and the presence of pain were assessed. The output frequency of the equipment was verified through oscilloscope tests. The control group received standard physical therapy intervention in the reference rehabilitation centre. Two physical therapists with extensive expertise applied the conventional treatment. Each session lasted approximately 60 min with the following structure: (1) Warm-up with cycle ergometer,10 min; (2) Stretching (20 s/2–3 repetitions) and passive/active-assisted upper and lower limb kinesiotherapy (3 series/10–15 repetitions), 10 min; (3) Bimanual exercises (e.g., task-specific exercises such as gripping and releasing objects, shoulder pulley, and elastic band training), 10 min; (4) Mobility and strengthening lower limb exercises (2–3 series, 10–15 repetitions), 10 min; (5) Coordination, balance and gait training, 20 min. The exercises were progressively adapted depending on the degree of motor function of the patient. | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8080700'] | ['33911100'] | [] | Statistical analyses included descriptive statistics and inferential analyses for group comparisons. Groups under study were compared in the four time points in several outcomes. Firstly, the groups under study were compared in their basal (pre-treatment) scores using one-way ANOVAs for quantitative variables and chi-square tests of independence for the qualitative ones. Secondly, several RM-MANOVAs were performed for each of the blocks of dependent variables: range of motion, hand strength, muscle tone, EMG activity, and motor function. Thirdly, when the RM-MANOVA resulted in a significant interaction of group and time in the dependent variables, follow-up mixed 3 (group) × 4 (time) ANOVAs were employed. In order for the treatments to be considered effective, the group × time interaction on the dependent variables should be statistically significant (p< .05) with control versus treatment differences. Compliance with parametric assumptions was ensured before ANOVAs were estimated. Independence of observations was assured by design (randomization). The assumptions of normality of residuals, constancy of the variance and sphericity were tested by plotting standardised residuals against factor levels, residuals vs. fitted values, and Q–Q plots of residuals, and testing the Sphericity assumption with Mauchly’s test. These analyses found that lack of normality or unequal group variances did not jeopardized the parametric analyses, and wherever the Sphericity assumption was not met the correction by Huyhn and Felt was employed. Additionally to statistical significance, effect sizes were calculated for all test statistics, specifically partial eta-squares were estimated (η2) for the effects and Cohen’s d for the comparisons of all pairs of means. Significant interactions were further scrutinised with mean comparisons with Bonferroni corrections. Thirdly, zero-order correlations were calculated among the 11 measures of motor impairment and the two functional measures (BBT and Barthel Index). | PMC8080700 | Article | null | 33,911,100 | A randomised clinical trial comparing 35 Hz versus 50 Hz frequency stimulation effects on hand motor recovery in older adults after stroke | Sentandreu-Mañó T, Tomás JM, Ricardo Salom Terrádez J. | Sci Rep. 2021 Apr 28;11(1):9131. doi: 10.1038/s41598-021-88607-8. | Sentandreu-Mañó T | Sci Rep | 2,021 | 2021/04/29 | PMC8080700 | null | 10.1038/s41598-021-88607-8 | oa_comm/txt/all/PMC8080700.txt | 1e815305846faefe057359df37b6b0ad | Sci Rep. 2021 Apr 28; 11:9131 | 2021-06-20 18:20:18 | CC BY | no |
['PMC8186315'] | ['34113336'] | ['B1', 'B2', 'B3', 'B4', 'B6', 'B7', 'B8', 'B10', 'B11', 'B12', 'B14', 'B15', 'B16', 'B17', 'B18', 'B21', 'B22', 'B24', 'B25'] | Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma, accounting for 30–40% of newly diagnosed cases worldwide (1). Although most patients achieve remission with R-CHOP (rituximab, cyclophosphamide, adriamycin and prednisone) immunochemotherapy, 10–15% exhibit primary refractory disease and 20–35% suffer a relapse (2). For those with relapsed/refractory (RR) DLBCL, the median overall survival (OS) was only 6.3 months with conventional therapy (3). Triple-hit lymphoma (THL) that carries concurrent MYC, BCL2 and BCL6 rearrangements is a relatively rare subset, identified in approximately 1% of DLBCL patients (4–6). These rearrangements result in highly aggressive clinical behavior, resistance to standard chemotherapy and extremely poor outcomes (7). Although high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) remains the standard treatment for RR DLBCL, a series of studies demonstrated no appreciable benefits or even inferior outcomes for patients with THL after ASCT (8–10). TP53 is an important tumor suppressor gene and is proven as an inferior prognostic factor in DLBCL (11). Novel therapeutic strategies are needed to improve survival for these patients with triple-hit RR DLBCL. CD19-specific chimeric antigen receptor (CAR19)-T cell therapy has offered a new paradigm for the treatment of RR DLBCL. Three second-generation CAR19-T cell products, axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) have got FDA-approval for DLBCL (12–14). A latest meta-analysis demonstrated that second-generation CAR19-T cell therapy attained a remarkable overall response rate (ORR 55–79%) in RR DLBCL (n = 306), and the median OS was 13.2 months (15). Subgroup analyses demonstrated that CAR19-T cell therapy exhibited consistent efficacy between doublt-hit or triple-hit lymphoma and standard-risk DLBCL, supporting its application in triple-hit RR DLBCL (16,17). The majority of CAR-T cells used in clinical trials to data are conducted by lentivirus or retrovirus.PiggyBactransposon system, as an emerging non-viral methodology for stable genetic modification of human T cells, possesses a large gene-capacity, simple and cost-effective manufacturing, and an inclination to stem-cell memory (SCM) phenotype (18–21). Preclinical studies suggested thatPiggyBac-generated CAR19-T cells had a potent activity against B-cell malignancies (22–24). However, the efficacy and safety ofpiggyBac-engineered CAR-T cells haven’t been reported in human clinical trials. Here, we report the first case with triple-hit RR DLBCL who has receivedpiggyBac-generated CAR19-T cell therapy and achieved durable complete remission (CR) for over 24 months. Whether maintenance treatment is favorable and how to administrate it after CAR19-T cell therapy are hotly debated issues in RR DLBCL. Preclinical studies demonstrated that lenalidomide could enhance antitumor function of CAR19-T cells for lymphoma (25). Lenalidomide has been approved as maintenance therapy after transplantation for multiple myeloma, but not reported as maintenance after CAR-T cell therapy. The patient obtained a CR in the 2nd month and demanded maintenance therapy. Therefore, we have pioneered oral lenalidomide in the patient after CAR19-T cell infusion, which is worth further exploration. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | ['f1', 'f1', 'f1'] | A 53-year-old Chinese male patient was diagnosed as follicular lymphoma (grade 3A, stage II, group B) in May 2017 and achieved first CR after two cycles of R-CHOP (Figure 1). After given four cycles of R-CHOP, the patient’s disease relapsed. The pathologic biopsy and immunohistochemistry (IHC) of celiac lymph nodes revealed DLBCL, activated B-cell (ABC) subtype, and overexpression of MYC, BCL2 and BCL6. Fluorescencein situhybridization (FISH) of the lymphoma tissues also detected the triple rearrangements. Second-generation sequencing of the paraffin-embeded lymphoma tissues indicated 68.70% of TP53 mutation. The patient receieved two cycles of R-ICE (rituximab, ifosfamide, carboplatine and etoposide), and obtained a second CR. Unfortunately, he failed to collect hematopoietic stem cells for ASCT, and his disease progressed again with bone marrow involvement in June 2018. He complained of pain and weakness of both lower limbs, especially the left lower extremity. Subsequently, one cycle of R-DHAP(rituximab, dexamethasone, cytarabine and cisplatine) was administrated. Symptoms of left peripheral facial paralysis and severe headache occurred, and supportive treatment showed no response. The patient then suffered left eyeball pain, but still kept complete self-cognition. Head computed tomography (CT) scans excluded elevated intraocular pressure and intracranial space-occupying lesions. Head magnetic resonance imaging, including plain and enhancement scans, didn’t show involvement of the brain parenchyma. The patient was unable to receive lumbar puncture and intrathecal chemotherapy because of pain and weakness of both lower limbs. He was given promptly with high-dose methotrexate intravenously once and single infusion of combined regimens including rituximab, high-dose methotrexate and cytarabine. Positron emission tomography (PET)-CT scans suggested extensive invasion of lymphoma in gastric wall, small intestines and bone marrow, scoring 5 points per Deauville criteria (Figure 1). Abdominal CT scans showed an abnormal mass sized as 3.0 × 2.2 cm (Figure 1). Repeated IHC of the paraffin-embeded lymphoma tissues was strongly positive for CD19. 1.5% of the cells were of unknown classification in bone marrow cytology, but no abnormal monoclonal B cells were found in bone marrow immunophenotyping. FISH showed the triple rearrangements of MYC, BCL2 and BCL6, and 4.51% of TP53 mutation was found in bone marrow. Cerebrospinal fluid examination didn’t indicate involvement in central nervous system. Therefore, the patient was enrolled in the phase 1 study (ChiCTR1800018111). | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | ['f2', 'B26'] | The CD19CAR incorporated an FMC63 mAb-derived single chain variable fragment, a human CD8α hinge and transmembrane domain, an intracellular 4-1BB (CD137) costimulatory domain, and a cytoplasmic CD3ζ signal (Figure 2). The CD19CAR gene was cloned into thePiggyBactransposon vector pNB328-EF1α to construct pNB328-CD19CAR, as described (26). Peripheral blood mononuclear cells were collected by leukapheresis from the patient and isolated by Ficoll density gradient centrifugation. T cells were electroporated with pNB328-CD19CAR plasmids and then activated by anti-CD3/CD28 antibodies in KBM581 medium containing 200 U/ml recombinant human interleukin (IL)-2 for 5 days. Thereafter, the activated cells were cultured until meeting the predefined release criteria, including transduction efficiency ≥5%, cell viability ≥70%, negative mycoplasma, negative bacterial and fungal cultures. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | ['f2', 'B27', 'f3', 'f3', 'f3', 'f3', 'f1', 'B28', 'f1', 'f3'] | The patient was given the lymphodepleting chemotherapy(fludarabine 50mg, days-5 to -3; cyclophosphamide 1,200 mg, day-3). On October 23, 2018 (day 0), the patient received an infusion ofpiggyBac-generated CAR19-T cells at the dose of 1.0 × 106/kg. In the final infused cell products, the CAR transfection efficiency was 42.97%, including 33.28% of CD4+CAR+cells and 13.54% of SCM T cells (Figure 2). During days 9 to 11 post-infusion, the patient experienced pyrexia, hypoxia and emesis with a maximum temperature of 39.3 °C, which was rated as grade 2 cytokine release syndrome (CRS) against Lee’s criteria (27). As the body temperature rose after infusion, serum IL-6 and C-reactive protein significantly elevated, peaked at 598.5 and 73.8 mg/l, respectively (36-fold and 9-fold over upper limit of normal) (Figure 3A). Therefore, intravenous tocilizumab 8 mg/kg and supportive treatment were administrated, and CRS got well controlled. The CAR copies increased dramatically and peaked at 103,000 copies/ug on day 14 (Figure 3). The peak of ferritin and lactate dehydrogenase were detected on day 24, later than the time when toxicity culminated (Figure 3D). Moreover, he developed grade 3–4 hematological toxicities, which were relieved during the 1st month (Figure 3). The patient obtained a partial remission (PR) in the 1st month per Lugano criteria (Figure 1D) (28). Bone marrow biopsy and immunophenotyping had no signs of lymphoma involvement, and only 0.5% of the cells of unknown classification were found in bone marrow cytology. In the 2nd month, PET-CT scans were consistent with a complete metabolic response, and abdominal CT scans were normal (Figure 1F). Bone marrow examination were normal, including biopsy, cytology, and immunophenotyping. TP53 mutation disappeared and FISH detected no abnormality in bone marrow. In the 3rd month, the patient maintained CR and demanded maintenance therapy. Oral lenadomide(25 mg/day, 21 days of 28-day cycle) was given in the 4th month and the patient discontinued after one-cycle administration due to side effects such as skin rashes, pruritus and painful joints. The CAR copies could be detected in peripheral blood until the 9th month post-infusion by quantitative polymerase chain reaction (Figure 3). The patient has still kept durable CR for over 24 months. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | ['B4', 'B5', 'B6', 'B7', 'B6', 'B29', 'B30', 'B31', 'T1', 'B12', 'B32', 'B13', 'B16', 'B33', 'B14', 'B14', 'B16', 'B17', 'B34', 'B35', 'B22', 'B24', 'B36', 'B37', 'B40', 'B21', 'B23', 'B41', 'B8', 'B10', 'B42', 'B44', 'B45', 'B46', 'B25', 'B47'] | To the best of our knowledge, this is the first case with triple-hit RR DLBCL who has receivedpiggyBac-generated CAR19-T cell therapy and maintained durable CR for over 24 months. It’s also the first report about oral lenalidomide maintenance after CAR-T cell infusion. The 2016 revised World Health Organization guidelines of lymphoid neoplasms classified large B-cell lymphoma with rearrangements of MYC and BCL2 or/and BCL6 in a distinct category to be designated high-grade B-cell lymphoma, also called double-hit lymphoma (DHL) or THL (4). DHL comprises approximately 2–10% of newly diagnosed DLBCL cases, and THL is a rare subset, accounting for almost 1% in DLBCL (5,6). The largest series of THL to data included 40 patients, suggesting that its clinicopathologic features were similar to DHL and TP53 mutation was an independent predictor of poor prognosis (7). Patients with DHL/THL have significantly suboptimal responses and dismal outcomes with standard first-line R-CHOP chemoimmunotherapy (6,29,30). Our case relapsed following initial CR to R-CHOP and transformed to triple-hit DLBCL. High-dose chemotherapy combined with ASCT has historically regarded as the curative chance for patients with chemotherapy-sensitive relapse (31). Therefore, our patient was given R-ICE as salvage regimens prior to ASCT, and the patient achieved second CR. Unfortunately, the patient failed in the bridge to ASCT, and suffered second recurrence, and even became resistant to another three lines of salvage chemotherapy. Novel therapeutic options are urgently needed for these patients with triple-hit RR DLBCL. CAR19-T cell therapy has emerged as a novel promising immunotherapy exhibiting remarkable efficacy in patients with chemotherapy-refractory DLBCL (Table 1). Axi-cel, as the first FDA-approved CAR19-T cell product for RR DLBCL, is generated untilizing retroviral vectors and contains a CD28 costimulation domain (12). In the pivotal ZUMA-1 trial, axi-cel showed a striking ORR and CR rate of 83 and 58% (n = 108), respectively. At a median follow-up of 27.1 months, 39% maintained ongoing remission, and the median OS didn’t reach. 93% of patients had CRS per Lee criteria (severe 11%), and 67% experienced neurotoxicity (severe 32%), both of which were manageable and largely reversible (32). Tisa-cel is the second FDA-approved CAR19-T cell product for DLBCL, which is manufactured using lentiviral vectors and a 4-1BB costimulation domain (13). In the pivotal JULIET study, 52% of patients achieved an objective response and 40% attained a CR (n = 93) at a median follow-up of 14 months. CRS occurred in 64% of patients (severe 22%) against the Penn grading scale, and neurotoxicity occurred in 23% of patients (severe 12%) (16). The lower incidence of CRS and neurotoxicity compared with axi-cel is possiblely related to 4-1BB costimulation domain ultilized in tisa-cel. Parallel comparison of 4-1BB or CD28 co-stimulated CAR19-T cells for B-cell lymphoma suggests that 4-1BB is more beneficial and tolerated for the clinical performance (33). Therefore, 4-1BB is widely applied in subsequent CAR-T cell products, including lisocabtagene maraleucel(liso-mar) and thepiggyBac-generated CAR19-T cells in our study. Liso-mar is being actively tested in B-cell lymphoma. In the TRANSCEND trial, liso-mar exhibited a high response rate (73%, n = 268) and low incidences of CRS (42%, severe 2%) and neurotoxicity (30%, severe 10%) (14). Subgroup analyses of the JULIET and TRANSCEND trials demonstrated that patients with DHL/THL responded as similarly well to CAR19-T cell therapy as standard-risk DLBCL (14,16,17). These results support the application of CAR19-T cell therapy in doublt-hit or triple-hit RR DLBCL. The majority of CAR-T cells used in clinical trials to data are conducted by lentivirus or retrovirus. Paralleled comparison of vectors for the generation of CAR-T cells was comprehensively reviewed (34). Viral vectors possess an ideal transduction efficiency and stable transgene expression, but to some extent, they also correlate with a high risk of insertional mutagenesis and potential malignant transformation. The novel non-viralPiggyBactransposon system, with decreased integration frequency into proto-oncogenes in human T cells, shows great application potential for stable genetic modification of human T cells (35).PiggyBacsystem consists of two components: a transposon plasmid carrying the target gene and another plasmid encoding the transposase, both of which are introduced into cells by electroporation. Preclinical studies suggested thatPiggyBac-generated CAR19-T cells had a potent activity against B-cell malignancies (22–24). However, the preliminary efficacy and safety ofpiggyBac-engineered CAR-T cells haven’t been reported in human clinical trials. Here, we report the first case with triple-hit RR DLBCL who has receivedpiggyBac-generated CAR19-T cell therapy. Limitedin vivoexpansion and persistence of CAR19-T cells is considered as a main possible mechanism of CD19-positive relapse after CAR19-T cell therapy (36). SCM T cells are known to promote superiorin vivoperliferation and survival of CAR-T cells (37–40). Previous studies indicated thatpiggyBacsystem had the preference to SCM T cells (21,23,41), thuspiggyBacsystem could be a feasible optimization for CAR-T manufacturing. In the case, the final infused cell products contained only 13.54% of SCM T cells and ownedin vivolifespan of 9 months, which inadequately explained the patient’s exceptional response. Whether maintenance treatment is favorable and how to administrate it after CAR19-T cell therapy are hotly debated issues in RR DLBCL. The patient obtained a CR in the 2nd month and demanded maintenance therapy. Despite ASCT recommended as the standard care for RR DLBCL, a series of studies demonstrated no appreciable benefits or even inferior outcomes for patients with DHL/THL after ASCT (8–10). Until now there is no evidence to support consolidation with transplantation after CAR-T cell therapy in lymphoma, hence novel strategies for maintenance therapy are warranted to explore. Lenalidomide, an oral immunomodulator, has been approved by FDA as maintenance therapy after ASCT for patients with multiple myeloma based on evidences from two randomized, blinded trials (CALGB100104 and IFM 2005-02) (42–44). Lenalidomide also exhibited activity as maintenance therapy in RR DLBCL, especially in ABC subtype for the reason that lenalidomide strongly inhibited NF-kB signaling, key pathogenesis of ABC subtype (45). Oral lenalidomide maintenance (25 mg/day, 21 days of 28-day cycle) after salvage chemotherapy in patients with RR DLBCL (n = 47) attained 1-year and 5-year PFS of 70 and 53%, respectively (46). Preclinical studies demonstrated that lenalidomide could enhance antitumor function of CAR19-T cells for aggressive B-cell lymphoma, whose mechanisms included augmented cytotoxicity, memory maintenance and persistence, and Th1 cytokine production (25). These results indicated that lenalidomide maintenance after CAR-T cells therapy deserved investigation. Therefore, we pioneered oral lenalidomide in the patient in the 4th month. The patient still maintains CR for over 2 years and his OS is over 3 years. Several limitations exist in the present study. First, this is a case report, and more cases are needed to observe the overall safety and efficacy ofpiggyBac-generated CAR19-T cell therapy in RR DLBCL. Second, the patient discontinued after one-cycle lenalidomide due to adverse reactions, thus the risks of lenolidomide shouldn’t be understated. A multicenter retrospective study indicated that lymphoma patients had similar benefits in ORR, PFS and OS when administrated with 10, 15 or 25 mg/day lenalidomide (47). Oral low-dose lenalidomide maintenance (10 mg) after CAR-T cell therapy deserves further exploration to minimize side reactions. Third, the additive role of lenalidomide maintenance after CAR-T cell therapy warrants controlled trials to verify. In conclusion, our case, for the first time, has demonstrated the feasibility, preliminary safety and efficacy ofpiggyBac-produced CAR19-T cell therapy in triple-hit lymphoma. Future investigations with large sample sizes are needed to clarify the overall safety and activity ofpiggyBac-genrated CAR19-T cell therapy in RR DLBCL, and the additive effects of lenalidomide maintenance. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | When I failed to prepare for ASCT, and then suffered the second relapse and didn’t respond to the following chemotherapy, I felt so helpless. The outcome of patients with RR DLBCL is dismal, especially for patients with MYC, BCL2 and BCL6 rearrangements and TP53 mutuation. I am glad to participate in the study and has received thepiggyBac-generated CAR19-T cell therapy. Although I attained CR in the 2nd month, I demanded maintenance treatment in view of my experience of two relapses. My doctors gave me oral lenalidomide in the 4th month, but I discontinued after one course due to some side effects. I still keep CR for over 2 years and I hope that my case will give some inspiration for physicians and patients all over the world. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | The studies involving human participants were reviewed and approved by the Ethics Committee of the Union Hospital affiliated to Huazhong University of Science and Technology, Wuhan, China. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | YH and HM conceived and designed the study. CL and YS performed data analysis and wrote the paper. JWa contributed imaging interpretation. LT and HJ performed data collection. TG, LL, YW, and LX participated in patient management. LA analyzed the flow results. JWa, ZL, and QQ provided the CAR19-T cell products. All authors contributed to the article and approved the submitted version. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | This work was supported by grants from Key Special Project of “Research on Prevention and Control of Major Chronic Non-infectious Diseases” (No. 2019YFC1316203 to HM, No. 2019YFC1316204 to YH). | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC8186315'] | ['34113336'] | [] | Authors YS, JW, ZL, and QQ are employed by Shanghai Cell Therapy Group Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC8186315 | Immunology; Case Report | null | 34,113,336 | PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report | Li C, Sun Y, Wang J, Tang L, Jiang H, Guo T, Liu L, Wu Y, Ai L, Xia L, Wu J, Lin Z, Qian Q, Hu Y, Mei H. | Front Immunol. 2021 May 25;12:599493. doi: 10.3389/fimmu.2021.599493. eCollection 2021. | Li C | Front Immunol | 2,021 | 2021/06/11 | PMC8186315 | null | 10.3389/fimmu.2021.599493 | oa_comm/txt/all/PMC8186315.txt | b86840ce165eb9d77328e75c64067534 | Front Immunol. 2021 May 25; 12:599493 | 2021-09-03 06:52:17 | CC BY | no |
['PMC7317929'] | ['31823444'] | [] | This was a multicenter, randomized, flexible‐dose, double‐blind, double‐dummy, 6‐week non‐inferiority study comparing the efficacy and safety of lurasidone to risperidone in the treatment of schizophrenia. The study was conducted at 16 investigational sites in China, with data collection occurring from January 2014 to April 2015. Following a screening visit, hospitalized patients who continued to meet study entry criteria after completion of a 7‐day washout period were randomized, in a 1:1 ratio, to 6 weeks of treatment with lurasidone (40 or 80 mg/day) or risperidone (2, 4, or 6 mg/day). Patients could remain in the hospital setting for the duration of the double‐blind treatment period, but patients considered by the investigator to be clinically stable could be discharged after 3 weeks. Study medication was provided as identically matched (in color, shape, size, and packaging) lurasidone or risperidone tablets. An interactive web response system used a computer‐generated list of random numbers to allocate study treatments. None of the investigators, study staff, or patients had access to the randomization codes or list during the study. Because of the difference in titration schedule for lurasidone and risperidone, a double‐dummy design was utilized to ensure that the double‐blind was maintained: patients randomized to lurasidone also received a risperidone‐matched placebo, and patients randomized to risperidone received a lurasidone‐matched placebo. Doses for both lurasidone and risperidone were administered orally once daily after dinner. The starting dose of lurasidone was 40 mg/day. After 6 days, the dose could be increased to 80 mg/day based on the patient's symptoms and tolerability. Risperidone was initiated at 2 mg/day. After 3 days, the dose was increased to 4 mg/day for 3 days. On day 7, the dose was increased to 6 mg/day or maintained at 4 mg/day, based on the patient's symptoms and tolerability. For both lurasidone and risperidone, the dose had to be increased to the higher dose at weeks 2, 3, or 4 if change from baseline on the PANSS was less than nine points (unless significant adverse events were present). The dose could be reduced at any time if intolerable adverse events occurred. The study was approved by an Ethics Committee at each investigational site, and written informed consent was obtained from all patients prior to any study procedures. For patients younger than age 20, written informed consent was also obtained from the patient's legal guardian. The study was conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-bib-0029', 'pcn12965-bib-0030'] | Eligible for the study were patients 18–65 years of age meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision edition (DSM‐IV‐TR) criteria for a primary diagnosis of schizophrenia. In addition, patients needed to have at both screening and baseline a score ≥ 4 on the Clinical Global Impression‐Severity scale29and a Positive and Negative Syndrome Scale (PANSS)30total score of ≥70 and ≤120, with a score of 4 (moderate) or higher on 2 or more items of the following PANSS items: delusions, conceptual disorganization, hallucinations, unusual thought content, and suspiciousness. Key exclusion criteria included any current clinically significant neurological, metabolic (including type 1 diabetes), hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, or urological disorders; HIV; alcohol abusers or alcohol dependency; long QT syndrome or required a drug that treats arrhythmia; prior history of poor clinical response and/or lack of tolerability to risperidone. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-bib-0029', 'pcn12965-bib-0031'] | The primary efficacy variable was the total score on the 30‐item clinician‐rated PANSS. Secondary efficacy variables included PANSS subscales (positive, negative), the Clinical Global Impression‐Severity of Illness (CGI‐S) and Clinical Global Impression‐Improvement scale (CGI‐I),29and the Calgary Depression Scale for Schizophrenia (CDSS).31Responder criteria consisted of ≥20% endpoint improvement in the PANSS total score. Efficacy measures were administered at screening, baseline, and at post‐baseline weeks 1, 2, 3, 4, and 6 (or study termination), with the exception of the CGI‐I, which was also administered at post‐baseline visits. In the present study, inefficacy was defined as worsening psychosis. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-bib-0032', 'pcn12965-bib-0030', 'pcn12965-bib-0033'] | Safety assessments included incidence of adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms (ECGs), body weight, laboratory tests (including HbA1C, lipids, prolactin, hematological indices), and urinalysis. AEs, body weight, and vital signs were assessed at every study visit (baseline, weeks 1, 2, 3, 4, and 6). ECGs and laboratory tests were performed at baseline, week 3, and week 6 (or last visit, if the patient discontinued prematurely). The clinician‐rated Barnes Akathisia Scale,32Abnormal Involuntary Movement Scale (AIMS),30and Simpson Angus Scale (SAS) (Simpson and Angus, 1970)33scales were used for evaluating akathisia, abnormal movement, and Parkinsonism, respectively. These scales were administered at baseline and weeks 1, 2, 3, 4, and 6. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | [] | As‐needed treatment was permitted for movement disorders, preferably, benzhexol (up to 15 mg/day); alternatively, biperiden (up to 16 mg/day) or diphenhydramine (up to 100 mg/day), could be used. Treatment with propranolol (up to 120 mg/day) or amantadine (up to 300 mg/day) was permitted as needed for akathisia. As‐needed use of benzodiazepines (lorazepam, zolpidem, and zopiclone) was permitted for severe anxiety, agitation, or insomnia. Anxiolytics, sedatives, or hypnotics were not to be administered within 12 h prior to an assessment visit. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-bib-0034', 'pcn12965-bib-0034', 'pcn12965-bib-0035', 'pcn12965-bib-0036', 'pcn12965-bib-0037'] | The intent‐to‐treat (ITT) efficacy analysis population was defined as all randomized patients who received at least one dose of study drug/medication and had at least one post‐baseline PANSS efficacy evaluation. A per‐protocol analysis population was defined as the subset of the ITT population that had been treated for 14 days or longer, had received 75% to 125% of study treatment, and had no major protocol violations. The safety population consisted of all randomized patients who received at least one dose of study medication. The primary efficacy endpoint was change from baseline to week 6 on the PANSS total score for the ITT sample. Non‐inferiority of lurasidone relative to risperidone was evaluated by comparing the upper boundary of the 95% confidence interval (CI) to a pre‐specified non‐inferiority margin of a difference of 7.0 PANSS total score points. A mixed model repeated measures (mmrm) method, including all weekly visits, was used to estimate the change to week 6. Themmrmincluded terms for treatment group, visit, center, baseline PANSS total score, and the treatment by visit interaction. An unstructured covariance matrix was specified for the within‐patient correlation, and the Kenward‐Rogers approximation was used for determining the denominator degrees of freedom. Because of potential bias when using an ITT sample to examine non‐inferiority, it has been recommended to examine non‐inferiority using a per‐protocol sample.34Accordingly, a supportivemmrmanalysis was also conducted on the per‐protocol sample for testing non‐inferiority. In addition to themmrm, a supportive analysis for the primary efficacy variable was conducted within the ITT sample using an analysis of covariance (ancova) model, with the last observation carried forward (LOCF) method applied for patients with no measurement at week 6. In theancovamodel, change from baseline to endpoint was set as the response variable and treatment, center, and baseline PANSS total scores were set as independent variables. Effect sizes were calculated using the Cohen's d statistic. Secondary efficacy variables were also analyzed within the ITT sample using anmmrmapproach similar to that conducted on the primary endpoint, except that standard superiority testing was conducted rather than inferiority testing. For the CGI‐I, no baseline score was included in the model. Confidence intervals (CI) around the estimated difference between the lurasidone and risperidone groups were calculated to evaluate whether the CI did not include zero (indicating superiority). Supportiveancovamodels (LOCF) were also performed on the secondary variables. Responder status was analyzed using logistic regression with treatment group as a categorical factor and baseline PANSS total score as a covariate. No adjustments were made for multiple comparisons. ancovamodels (LOCF) with treatment, center, and relevant baseline scores were used to analyze the change from baseline to endpoint on the following safety variables: BARNES total score, AIMS total score, and SAS total score. Non‐parametric rankanova(LOCF) was used to analyze selected laboratory analytes, body mass index (BMI), and body weight. The analysis of all other safety variables was descriptive. The target sample size was based on statistical power analysis for the non‐inferiority comparison of lurasidone and risperidone on the primary endpoint and incorporated the pre‐specified margin and estimates of the common standard deviation (SD) and attrition. The non‐inferiority margin of 7 points on the PANSS total score was based on the International Conference of Harmonization E9 guideline (International Conference on Harmonization E9 Expert Working Group)34and was similar to that used in previous trials with risperidone in which the margin has ranged from 6 to 7.3.35,36,37A common SD of 20 on change on the PANSS total score was derived from a previous lurasidone clinical trial. Using these values together with an estimated discontinuation rate of 20%, the total sample size was calculated to be 380 patients (190 per group) to have 85% power at the 2.5% significance level. For safety analysis, the occurrence rates of adverse events were compared using the χ2test or Fisher's Exact test as appropriate. Number needed to harm (NNH) values were calculated as the reciprocal of the difference in the prevalence of each adverse event. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-fig-0001', 'pcn12965-tbl-0001'] | There were 444 patients screened for the study; of these, 388 (87.4%) were randomized (194 in each treatment group; Fig.1). In the risperidone group, three patients did not receive the study drug and were excluded from the safety analysis population, and four patients did not have a post‐baseline assessment and were excluded from the intent‐to‐treat (ITT) population. A total of 54 patients (13.9%) discontinued treatment prior to 6 weeks (28 (14.4%) in the lurasidone group; 26 (13.4%) in the risperidone group). The median days of exposure to study drug for the safety analysis population was 42 days for each treatment group, with approximately 90% of patients receiving ≥29 days of study treatment (89.7% for lurasidone; 90.1% for risperidone). The ITT population was approximately 50% male, with a mean age of 35 years (Table1). The majority of patients were diagnosed with paranoid‐type schizophrenia (58.9%), followed by undifferentiated type (40.9%). No notable differences were observed between the treatment groups in baseline characteristics. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-tbl-0002', 'pcn12965-tbl-0002', 'pcn12965-tbl-0002', 'pcn12965-tbl-0002', 'pcn12965-fig-0002', 'pcn12965-fig-0003', 'pcn12965-fig-0004', 'pcn12965-fig-0005', 'pcn12965-fig-0006', 'pcn12965-fig-0007'] | Results of the primary (mmrm) efficacy analysis on the ITT population found that lurasidone meta prioricriteria for non‐inferiority to risperidone (Table2). The mean between‐treatment group difference in endpoint PANSS change scores was 3.7 (95%‐CI, 1.0–6.3). Criteria for non‐inferiority were met because the upper boundary of the 95%‐confidence interval (6.3) was less than the pre‐specified margin of 7.0. Criteria for non‐inferiority were also met based on an analysis of the per‐protocol population, with a mean between‐treatment group difference of 3.7 points (95% CI: 1.1, 6.4). The results of the supportiveancovaanalysis of the PANSS total score were consistent with themmrmanalysis, with a treatment difference of 3.0 points (Table2). Changes from baseline were statistically significant (P< 0.001) in both treatment groups at all post‐baseline assessment time‐points. The majority of patients met responder criteria at endpoint in the lurasidoneversusrisperidone groups (86.1% vs 91.1%), with no significant difference between the groups based on a logistic regression analysis. Secondary efficacy analyses for superiority yielded results that were largely consistent with the primary (non‐inferiority) analysis of PANSS total score. There were no significant differences between the treatment groups in change from baseline to week 6 for the CGI‐S, CGI‐I, PANSS negative subscale, or CDSS in either themmrmorancovaanalyses (Table2). As shown in Table2, between‐group significance was demonstrated at endpoint in favor for risperidone in themmrmanalyses of the PANSS total score and positive and negative subscale scores, however these findings of significance were based on nominalP‐values not corrected for multiple comparisons; and, furthermore, were not confirmed based on the supportiveancovaanalyses of each comparison. Change over time during the 6 weeks of study treatment is displayed in a series of figures for the PANSS total score (Fig.2), PANSS Positive subscale score (Fig.3), PANSS Negative subscale score (Fig.4), PANSS General Psychopathology subscale score (Fig.5), CGI‐Severity score (Fig.6; and CGI‐Improvement score), and CDSS total score (Fig.7). | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-tbl-0003', 'pcn12965-tbl-0003'] | The incidence of treatment‐emergent adverse events was numerically higher in the risperidone group (lurasidone: 69.1%; risperidone: 83.8%;P< 0.001; NNH = 7) (Table3). One serious adverse event (SAE; fracture of the hand) occurred among lurasidone‐treated patients and was judged not related to treatment. No SAEs occurred in the risperidone‐treated patients. No deaths were reported on either drug. Adverse events leading to discontinuation were reported in 2.1% of patients in the lurasidone group and 4.7% of those in the risperidone group. The majority of adverse events were rated as either mild or moderate. Events rated as severe were reported in 2.1% of patients in the lurasidone group and 1.0% of those in the risperidone group. EPS‐related adverse events occurred at a lower rate in the lurasidoneversusrisperidone group (26.3% vs 46.1%;P< 0.001; NNH = 6; Table3). During 6 weeks of study treatment, no clinically meaningful baseline‐to‐endpoint changes, or between‐treatment group differences, were found for vital signs, hematology parameters, HbA1c, HDL, LDL, total cholesterol, triglycerides, ECG, or urinalysis parameters. For risperidoneversuslurasidone, there was significant endpoint increase in glucose (+1.1 mg/dL vs −0.3 mg/dL;P< 0.05), serum prolactin (+60.4 ng/mL vs +3.5 ng/mL;P< 0.001), and body mass index (+0.45 kg/m2vs +0.20 kg/m2;P< 0.05). [Correction added on 27 April 2020, after first online publication: Body mass index has been amended.] Analysis of change from baseline to week 6 (LOCF) on the BARNES, AIMS, and SAS revealed no significant differences between the lurasidone and risperidone groups (+0.2 vs +0.2,P= 0.369; +0.0 vs +0.0,P= 0.922; +0.5 vs +0.8,P= 0.098). | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | ['pcn12965-bib-0021', 'pcn12965-bib-0018', 'pcn12965-bib-0021', 'pcn12965-bib-0011', 'pcn12965-bib-0012', 'pcn12965-bib-0013', 'pcn12965-bib-0014', 'pcn12965-bib-0015', 'pcn12965-bib-0018'] | This 6‐week, randomized, double‐blind, non‐inferiority trial evaluated the efficacy and safety of flexibly dosed lurasidone (40 mg/day or 80 mg/day) in comparison to risperidone (2, 4, or 6 mg/day) in patients with schizophrenia in China. On the primary efficacy endpoint, the non‐inferiority of lurasidone relative to risperidone was demonstrated in both the ITT population (primary analysis) and the per‐protocol population. Interpretation of non‐inferiority studies can be difficult because of potential bias in ITT and per‐protocol analyses. However, our confidence in the finding of non‐inferiority is increased due to the consistency of the results for both analysis populations, due to the low overall study discontinuation rate (13.9%; similar for both treatments), and because treatment compliance was similar for the two treatments. Larger sample sizes are required to perform non‐inferiority testing when compared to sample sizes required in studies designed as superiority trials. Despite the high degree of power associated with large sample sizes used in the current study, superiority testing of secondary efficacy measures revealed no statistically significant between‐treatment group difference, with one exception: there was a small difference favoring risperidone on the PANSS positive subscale. This finding, however, was only evident in themmrmanalysis but not in theancovaanalysis. Thus, overall, the results of this study suggest that the efficacy of lurasidone is comparable to risperidone in the treatment of schizophrenia in Chinese patients. Our results are consistent with a recent network meta‐analysis, reporting similar changes in overall symptoms for lurasidone and risperidone in the treatment of schizophrenia.21It should be noted that the meta‐analysis only included studies of patients with acute schizophrenia, while the present study recruited both acute and chronic patients having positive symptoms. Nevertheless, the effect sizes for lurasidoneversusrisperidone on PANSS reported by the two studies were comparable (0.22 vs 0.19). The safety profile for lurasidone among Chinese patients in the current study was consistent with previous lurasidone studies, with no new safety/tolerability concerns evident. Lurasidone was found to have a more favorable safety profile than risperidone. In particular, there was a lower incidence of EPS and metabolic events, particularly weight increase, and less change in serum prolactin levels, for lurasidone compared to risperidone. These different effects on body weight and prolactin levels replicate those reported in a 12‐month safety trial comparing lurasidone and risperidone,18and are in line with the results of a previous network meta‐analysis.21Our findings are also consistent with the minimal impact on EPS, metabolic parameters, and weight reported for lurasidone in multiple, previous placebo‐controlled trials.11,12,13,14,15 The current findings should be understood in light of several limitations of the present study. All sites were in China, and therefore results should not be generalized to patient populations in other countries. Nevertheless, previous studies have yielded similar safety results in other countries.18In addition, study entry criteria excluded patients with concurrent acute medical and psychiatric conditions, which may limit the generalizability of the current results in the subgroup of patients with schizophrenia in the community with medical or psychiatric comorbidity. In addition, both acute and chronic patients having positive symptoms were included, which might influence the results of the efficacy study. Nevertheless, because of the randomized design, this heterogeneity is expected to be balanced between the two groups. Finally, the study duration was too short (6 weeks) to provide an adequate assessment of the effect of study treatment on negative symptoms. In conclusion, the current study found lurasidone to be non‐inferior to risperidone in terms of antipsychotic efficacy among Chinese patients with schizophrenia. In addition, a more favorable safety profile was evident for lurasidone compared with risperidone, with a lower incidence of EPS, less weight increase, and less change in serum prolactin levels. Thus, lurasidone would appear to offer a useful treatment option for Chinese patients with schizophrenia, with comparable efficacy and improved safety and tolerability consistent with a favorable benefit–risk profile. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | [] | The authors declare no conflict of interest. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
['PMC7317929'] | ['31823444'] | [] | All authors were involved in the acquisition and interpretation of the data, and the development and revision of the manuscript; and have approved the final version. | PMC7317929 | Regular Article; Regular Articles | null | 31,823,444 | Randomized, double-blind, 6-week non-inferiority study of lurasidone and risperidone for the treatment of schizophrenia | Feng Y, Shi J, Wang L, Zhang X, Tan Y, Zhao J, Ning Y, Xie S, Liu X, Liu Q, Li K, Wang X, Li L, Xu X, Deng W, Luo X, Wang G. | Psychiatry Clin Neurosci. 2020 Jun;74(6):336-343. doi: 10.1111/pcn.12965. Epub 2020 Jan 8. | Feng Y | Psychiatry Clin Neurosci | 2,020 | 2019/12/12 | PMC7317929 | null | 10.1111/pcn.12965 | oa_comm/txt/all/PMC7317929.txt | d2cdde05c6901a842032412e353b7a8a | Psychiatry Clin Neurosci. 2020 Jun 8; 74(6):336-343 | 2021-06-19 05:43:43 | CC BY | no |
Subsets and Splits